Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.
Retrovirus-associated DNA sequences (abl) originally isolated from the Abelson murine leukemia virus (Ab-MuLV). The proto-oncogene abl (c-abl) codes for a protein that is a member of the tyrosine kinase family. The human c-abl gene is located at 9q34.1 on the long arm of chromosome 9. It is activated by translocation to bcr on chromosome 22 in chronic myelogenous leukemia.
Translation products of a fusion gene derived from CHROMOSOMAL TRANSLOCATION of C-ABL GENES to the genetic locus of the breakpoint cluster region gene on chromosome 22. Several different variants of the bcr-abl fusion proteins occur depending upon the precise location of the chromosomal breakpoint. These variants can be associated with distinct subtypes of leukemias such as PRECURSOR CELL LYMPHOBLASTIC LEUKEMIA-LYMPHOMA; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; and NEUTROPHILIC LEUKEMIA, CHRONIC.
The adherence and merging of cell membranes, intracellular membranes, or artificial membranes to each other or to viruses, parasites, or interstitial particles through a variety of chemical and physical processes.
Proteins, usually glycoproteins, found in the viral envelopes of a variety of viruses. They promote cell membrane fusion and thereby may function in the uptake of the virus by cells.
Fusion of somatic cells in vitro or in vivo, which results in somatic cell hybridization.
Clonal hematopoetic disorder caused by an acquired genetic defect in PLURIPOTENT STEM CELLS. It starts in MYELOID CELLS of the bone marrow, invades the blood and then other organs. The condition progresses from a stable, more indolent, chronic phase (LEUKEMIA, MYELOID, CHRONIC PHASE) lasting up to 7 years, to an advanced phase composed of an accelerated phase (LEUKEMIA, MYELOID, ACCELERATED PHASE) and BLAST CRISIS.
Proto-oncogene protein bcr is a serine-threonine kinase that functions as a negative regulator of CELL PROLIFERATION and NEOPLASTIC CELL TRANSFORMATION. It is commonly fused with cellular abl protein to form BCR-ABL FUSION PROTEINS in PHILADELPHIA CHROMOSOME positive LEUKEMIA patients.
Non-receptor tyrosine kinases encoded by the C-ABL GENES. They are distributed in both the cytoplasm and the nucleus. c-Abl plays a role in normal HEMATOPOIESIS especially of the myeloid lineage. Oncogenic transformation of c-abl arises when specific N-terminal amino acids are deleted, releasing the kinase from negative regulation.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
The GENETIC TRANSLATION products of the fusion between an ONCOGENE and another gene. The latter may be of viral or cellular origin.
A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.
The GENETIC RECOMBINATION of the parts of two or more GENES resulting in a gene with different or additional regulatory regions, or a new chimeric gene product. ONCOGENE FUSION includes an ONCOGENE as at least one of the fusion partners and such gene fusions are often detected in neoplastic cells and are transcribed into ONCOGENE FUSION PROTEINS. ARTIFICIAL GENE FUSION is carried out in vitro by RECOMBINANT DNA technology.
Operative immobilization or ankylosis of two or more vertebrae by fusion of the vertebral bodies with a short bone graft or often with diskectomy or laminectomy. (From Blauvelt & Nelson, A Manual of Orthopaedic Terminology, 5th ed, p236; Dorland, 28th ed)
The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.
An aberrant form of human CHROMOSOME 22 characterized by translocation of the distal end of chromosome 9 from 9q34, to the long arm of chromosome 22 at 22q11. It is present in the bone marrow cells of 80 to 90 per cent of patients with chronic myelocytic leukemia (LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE).
An advanced phase of chronic myelogenous leukemia, characterized by a rapid increase in the proportion of immature white blood cells (blasts) in the blood and bone marrow to greater than 30%.
Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.
Established cell cultures that have the potential to propagate indefinitely.
Transforming proteins encoded by the abl oncogenes. Oncogenic transformation of c-abl to v-abl occurs by insertional activation that results in deletions of specific N-terminal amino acids.
Proteins that catalyze MEMBRANE FUSION.
Protein analogs and derivatives of the Aequorea victoria green fluorescent protein that emit light (FLUORESCENCE) when excited with ULTRAVIOLET RAYS. They are used in REPORTER GENES in doing GENETIC TECHNIQUES. Numerous mutants have been made to emit other colors or be sensitive to pH.
The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.
Proteins which are involved in the phenomenon of light emission in living systems. Included are the "enzymatic" and "non-enzymatic" types of system with or without the presence of oxygen or co-factors.
A type of chromosome aberration characterized by CHROMOSOME BREAKAGE and transfer of the broken-off portion to another location, often to a different chromosome.
IMMUNOGLOBULINS on the surface of B-LYMPHOCYTES. Their MESSENGER RNA contains an EXON with a membrane spanning sequence, producing immunoglobulins in the form of type I transmembrane proteins as opposed to secreted immunoglobulins (ANTIBODIES) which do not contain the membrane spanning segment.
A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.
Cell changes manifested by escape from control mechanisms, increased growth potential, alterations in the cell surface, karyotypic abnormalities, morphological and biochemical deviations from the norm, and other attributes conferring the ability to invade, metastasize, and kill.
Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.
The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.
The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in leukemia.
The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.
A specific pair of GROUP G CHROMOSOMES of the human chromosome classification.
Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.
The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.
The parts of a macromolecule that directly participate in its specific combination with another molecule.
Progenitor cells from which all blood cells derive.
A myelodysplastic/myeloproliferative disorder characterized by myelodysplasia associated with bone marrow and peripheral blood patterns similar to CHRONIC MYELOID LEUKEMIA, but cytogenetically lacking a PHILADELPHIA CHROMOSOME or bcr/abl fusion gene (GENES, ABL).
Regions of AMINO ACID SEQUENCE similarity in the SRC-FAMILY TYROSINE KINASES that fold into specific functional tertiary structures. The SH1 domain is a CATALYTIC DOMAIN. SH2 and SH3 domains are protein interaction domains. SH2 usually binds PHOSPHOTYROSINE-containing proteins and SH3 interacts with CYTOSKELETAL PROTEINS.
Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.
Periplasmic proteins that bind MALTOSE and maltodextrin. They take part in the maltose transport system of BACTERIA.
Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity.
Extrachromosomal, usually CIRCULAR DNA molecules that are self-replicating and transferable from one organism to another. They are found in a variety of bacterial, archaeal, fungal, algal, and plant species. They are used in GENETIC ENGINEERING as CLONING VECTORS.
DNA molecules capable of autonomous replication within a host cell and into which other DNA sequences can be inserted and thus amplified. Many are derived from PLASMIDS; BACTERIOPHAGES; or VIRUSES. They are used for transporting foreign genes into recipient cells. Genetic vectors possess a functional replicator site and contain GENETIC MARKERS to facilitate their selective recognition.
Proteins prepared by recombinant DNA technology.
A rare myeloproliferative disorder that is characterized by a sustained, mature neutrophilic leukocytosis. No monocytosis, EOSINOPHILIA, or basophilia is present, nor is there a PHILADELPHIA CHROMOSOME or bcr-abl fusion gene (GENES, ABL).
A transferase that catalyzes the addition of aliphatic, aromatic, or heterocyclic FREE RADICALS as well as EPOXIDES and arene oxides to GLUTATHIONE. Addition takes place at the SULFUR. It also catalyzes the reduction of polyol nitrate by glutathione to polyol and nitrite.
Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.
A specific pair of GROUP C CHROMSOMES of the human chromosome classification.
The GENETIC RECOMBINATION of the parts of two or more GENES, including an ONCOGENE as at least one of the fusion partners. Such gene fusions are often detected in neoplastic cells and are transcribed into ONCOGENE FUSION PROTEINS.
Short sequences (generally about 10 base pairs) of DNA that are complementary to sequences of messenger RNA and allow reverse transcriptases to start copying the adjacent sequences of mRNA. Primers are used extensively in genetic and molecular biology techniques.
Eukaryotic cell line obtained in a quiescent or stationary phase which undergoes conversion to a state of unregulated growth in culture, resembling an in vitro tumor. It occurs spontaneously or through interaction with viruses, oncogenes, radiation, or drugs/chemicals.
RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.
The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.
Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.
Leukemia induced experimentally in animals by exposure to leukemogenic agents, such as VIRUSES; RADIATION; or by TRANSPLANTATION of leukemic tissues.
Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.
One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.
A non-essential amino acid. In animals it is synthesized from PHENYLALANINE. It is also the precursor of EPINEPHRINE; THYROID HORMONES; and melanin.
Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.
A multilineage cell growth factor secreted by LYMPHOCYTES; EPITHELIAL CELLS; and ASTROCYTES which stimulates clonal proliferation and differentiation of various types of blood and tissue cells.
Proteins coded by oncogenes. They include proteins resulting from the fusion of an oncogene and another gene (ONCOGENE PROTEINS, FUSION).
The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.
A cell line derived from cultured tumor cells.
A progressive, malignant disease of the blood-forming organs, characterized by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias were originally termed acute or chronic based on life expectancy but now are classified according to cellular maturity. Acute leukemias consist of predominately immature cells; chronic leukemias are composed of more mature cells. (From The Merck Manual, 2006)
Transport proteins that carry specific substances in the blood or across cell membranes.
The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.
Genes whose gain-of-function alterations lead to NEOPLASTIC CELL TRANSFORMATION. They include, for example, genes for activators or stimulators of CELL PROLIFERATION such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of "v-" before oncogene symbols indicates oncogenes captured and transmitted by RETROVIRUSES; the prefix "c-" before the gene symbol of an oncogene indicates it is the cellular homolog (PROTO-ONCOGENES) of a v-oncogene.
A group of enzymes that catalyzes the hydrolysis of terminal, non-reducing beta-D-galactose residues in beta-galactosides. Deficiency of beta-Galactosidase A1 may cause GANGLIOSIDOSIS, GM1.
A signal transducer and activator of transcription that mediates cellular responses to a variety of CYTOKINES. Stat5 activation is associated with transcription of CELL CYCLE regulators such as CYCLIN KINASE INHIBITOR P21 and anti-apoptotic genes such as BCL-2 GENES. Stat5 is constitutively activated in many patients with acute MYELOID LEUKEMIA.
Proteins found in any species of bacterium.
The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.
Substances that inhibit or prevent the proliferation of NEOPLASMS.
Resistance or diminished response of a neoplasm to an antineoplastic agent in humans, animals, or cell or tissue cultures.
Single-stranded complementary DNA synthesized from an RNA template by the action of RNA-dependent DNA polymerase. cDNA (i.e., complementary DNA, not circular DNA, not C-DNA) is used in a variety of molecular cloning experiments as well as serving as a specific hybridization probe.
A neoplasm characterized by abnormalities of the lymphoid cell precursors leading to excessive lymphoblasts in the marrow and other organs. It is the most common cancer in children and accounts for the vast majority of all childhood leukemias.
The entering of cells by viruses following VIRUS ATTACHMENT. This is achieved by ENDOCYTOSIS, by direct MEMBRANE FUSION of the viral membrane with the CELL MEMBRANE, or by translocation of the whole virus across the cell membrane.
CELL LINES derived from the CV-1 cell line by transformation with a replication origin defective mutant of SV40 VIRUS, which codes for wild type large T antigen (ANTIGENS, POLYOMAVIRUS TRANSFORMING). They are used for transfection and cloning. (The CV-1 cell line was derived from the kidney of an adult male African green monkey (CERCOPITHECUS AETHIOPS).)
Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.
Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation.
Form of leukemia characterized by an uncontrolled proliferation of the myeloid lineage and their precursors (MYELOID PROGENITOR CELLS) in the bone marrow and other sites.
The major protein constituents of milk are CASEINS and whey proteins such as LACTALBUMIN and LACTOGLOBULINS. IMMUNOGLOBULINS occur in high concentrations in COLOSTRUM and in relatively lower concentrations in milk. (Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed, p554)
Agents that inhibit PROTEIN KINASES.
In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships.
A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.
Layers of protein which surround the capsid in animal viruses with tubular nucleocapsids. The envelope consists of an inner layer of lipids and virus specified proteins also called membrane or matrix proteins. The outer layer consists of one or more types of morphological subunits called peplomers which project from the viral envelope; this layer always consists of glycoproteins.
A species of CERCOPITHECUS containing three subspecies: C. tantalus, C. pygerythrus, and C. sabeus. They are found in the forests and savannah of Africa. The African green monkey (C. pygerythrus) is the natural host of SIMIAN IMMUNODEFICIENCY VIRUS and is used in AIDS research.
Crystallizable fragments composed of the carboxy-terminal halves of both IMMUNOGLOBULIN HEAVY CHAINS linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (COMPLEMENT fixation, binding to the cell membrane via FC RECEPTORS, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme PAPAIN.
The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.
Microscopy of specimens stained with fluorescent dye (usually fluorescein isothiocyanate) or of naturally fluorescent materials, which emit light when exposed to ultraviolet or blue light. Immunofluorescence microscopy utilizes antibodies that are labeled with fluorescent dye.
Conditions which cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. They all involve dysregulation of multipotent MYELOID PROGENITOR CELLS, most often caused by a mutation in the JAK2 PROTEIN TYROSINE KINASE.
The rate dynamics in chemical or physical systems.
Serologic tests in which a positive reaction manifested by visible CHEMICAL PRECIPITATION occurs when a soluble ANTIGEN reacts with its precipitins, i.e., ANTIBODIES that can form a precipitate.
Cell lines whose original growing procedure consisted being transferred (T) every 3 days and plated at 300,000 cells per plate (J Cell Biol 17:299-313, 1963). Lines have been developed using several different strains of mice. Tissues are usually fibroblasts derived from mouse embryos but other types and sources have been developed as well. The 3T3 lines are valuable in vitro host systems for oncogenic virus transformation studies, since 3T3 cells possess a high sensitivity to CONTACT INHIBITION.
A broad category of carrier proteins that play a role in SIGNAL TRANSDUCTION. They generally contain several modular domains, each of which having its own binding activity, and act by forming complexes with other intracellular-signaling molecules. Signal-transducing adaptor proteins lack enzyme activity, however their activity can be modulated by other signal-transducing enzymes
The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for VIRUS CULTIVATION and antitumor drug screening assays.
The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport.
Deletion of sequences of nucleic acids from the genetic material of an individual.
Family of RNA viruses that infects birds and mammals and encodes the enzyme reverse transcriptase. The family contains seven genera: DELTARETROVIRUS; LENTIVIRUS; RETROVIRUSES TYPE B, MAMMALIAN; ALPHARETROVIRUS; GAMMARETROVIRUS; RETROVIRUSES TYPE D; and SPUMAVIRUS. A key feature of retrovirus biology is the synthesis of a DNA copy of the genome which is integrated into cellular DNA. After integration it is sometimes not expressed but maintained in a latent state (PROVIRUSES).
A broad category of proteins involved in the formation, transport and dissolution of TRANSPORT VESICLES. They play a role in the intracellular transport of molecules contained within membrane vesicles. Vesicular transport proteins are distinguished from MEMBRANE TRANSPORT PROTEINS, which move molecules across membranes, by the mode in which the molecules are transported.
DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.
Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)
Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme.
Use of restriction endonucleases to analyze and generate a physical map of genomes, genes, or other segments of DNA.
Diffusible gene products that act on homologous or heterologous molecules of viral or cellular DNA to regulate the expression of proteins.
Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.
Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (BIOMARKERS, TUMOR) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm.
Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are linear polypeptides that are normally synthesized on RIBOSOMES.
Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.
Cells contained in the bone marrow including fat cells (see ADIPOCYTES); STROMAL CELLS; MEGAKARYOCYTES; and the immediate precursors of most blood cells.
A superfamily of small proteins which are involved in the MEMBRANE FUSION events, intracellular protein trafficking and secretory processes. They share a homologous SNARE motif. The SNARE proteins are divided into subfamilies: QA-SNARES; QB-SNARES; QC-SNARES; and R-SNARES. The formation of a SNARE complex (composed of one each of the four different types SNARE domains (Qa, Qb, Qc, and R)) mediates MEMBRANE FUSION. Following membrane fusion SNARE complexes are dissociated by the NSFs (N-ETHYLMALEIMIDE-SENSITIVE FACTORS), in conjunction with SOLUBLE NSF ATTACHMENT PROTEIN, i.e., SNAPs (no relation to SNAP 25.)
An amino acid that occurs in endogenous proteins. Tyrosine phosphorylation and dephosphorylation plays a role in cellular signal transduction and possibly in cell growth control and carcinogenesis.
Procedures by which protein structure and function are changed or created in vitro by altering existing or synthesizing new structural genes that direct the synthesis of proteins with sought-after properties. Such procedures may include the design of MOLECULAR MODELS of proteins using COMPUTER GRAPHICS or other molecular modeling techniques; site-specific mutagenesis (MUTAGENESIS, SITE-SPECIFIC) of existing genes; and DIRECTED MOLECULAR EVOLUTION techniques to create new genes.
The transfer of bacterial DNA by phages from an infected bacterium to another bacterium. This also refers to the transfer of genes into eukaryotic cells by viruses. This naturally occurring process is routinely employed as a GENE TRANSFER TECHNIQUE.
Antibodies produced by a single clone of cells.
The arrangement of two or more amino acid or base sequences from an organism or organisms in such a way as to align areas of the sequences sharing common properties. The degree of relatedness or homology between the sequences is predicted computationally or statistically based on weights assigned to the elements aligned between the sequences. This in turn can serve as a potential indicator of the genetic relatedness between the organisms.
A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.
Myeloid-lymphoid leukemia protein is a transcription factor that maintains high levels of HOMEOTIC GENE expression during development. The GENE for myeloid-lymphoid leukemia protein is commonly disrupted in LEUKEMIA and combines with over 40 partner genes to form FUSION ONCOGENE PROTEINS.
Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.
Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus.
Proteins found in any species of virus.
Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.
Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques.
The phase of chronic myeloid leukemia following the chronic phase (LEUKEMIA, MYELOID, CHRONIC-PHASE), where there are increased systemic symptoms, worsening cytopenias, and refractory LEUKOCYTOSIS.
ATPases that are members of the AAA protein superfamily (ATPase family Associated with various cellular Activities). The NSFs functions, acting in conjunction with SOLUBLE NSF ATTACHMENT PROTEINS (i.e. SNAPs, which have no relation to SNAP 25), are to dissociate SNARE complexes.
A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement.
A transcription factor that dimerizes with the cofactor CORE BINDING FACTOR BETA SUBUNIT to form core binding factor. It contains a highly conserved DNA-binding domain known as the runt domain. Runx1 is frequently mutated in human LEUKEMIAS.
Immunologic method used for detecting or quantifying immunoreactive substances. The substance is identified by first immobilizing it by blotting onto a membrane and then tagging it with labeled antibodies.
Proteins which maintain the transcriptional quiescence of specific GENES or OPERONS. Classical repressor proteins are DNA-binding proteins that are normally bound to the OPERATOR REGION of an operon, or the ENHANCER SEQUENCES of a gene until a signal occurs that causes their release.
Electrophoresis in which a polyacrylamide gel is used as the diffusion medium.
Glycoproteins found on the membrane or surface of cells.
The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).
CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells.
Normal cellular genes homologous to viral oncogenes. The products of proto-oncogenes are important regulators of biological processes and appear to be involved in the events that serve to maintain the ordered procession through the cell cycle. Proto-oncogenes have names of the form c-onc.
A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).
Glycoproteins found on immature hematopoietic cells and endothelial cells. They are the only molecules to date whose expression within the blood system is restricted to a small number of progenitor cells in the bone marrow.
Mice homozygous for the mutant autosomal recessive gene "scid" which is located on the centromeric end of chromosome 16. These mice lack mature, functional lymphocytes and are thus highly susceptible to lethal opportunistic infections if not chronically treated with antibiotics. The lack of B- and T-cell immunity resembles severe combined immunodeficiency (SCID) syndrome in human infants. SCID mice are useful as animal models since they are receptive to implantation of a human immune system producing SCID-human (SCID-hu) hematochimeric mice.
Proteins found in any species of fungus.
A promyelocytic cell line derived from a patient with ACUTE PROMYELOCYTIC LEUKEMIA. HL-60 cells lack specific markers for LYMPHOID CELLS but express surface receptors for FC FRAGMENTS and COMPLEMENT SYSTEM PROTEINS. They also exhibit phagocytic activity and responsiveness to chemotactic stimuli. (From Hay et al., American Type Culture Collection, 7th ed, pp127-8)
A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair.
The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990)
Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.
Serine-threonine protein kinases that relay signals from CYTOKINE RECEPTORS and are involved in control of CELL GROWTH PROCESSES; CELL DIFFERENTIATION; and APOPTOSIS.
Glycoprotein from Sendai, para-influenza, Newcastle Disease, and other viruses that participates in binding the virus to cell-surface receptors. The HN protein possesses both hemagglutinin and neuraminidase activity.
The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of IgG, for example, IgG1, IgG2A, and IgG2B.
The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.
The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.
Elements of limited time intervals, contributing to particular results or situations.
The initial phase of chronic myeloid leukemia consisting of an relatively indolent period lasting from 4 to 7 years. Patients range from asymptomatic to those exhibiting ANEMIA; SPLENOMEGALY; and increased cell turnover. There are 5% or fewer blast cells in the blood and bone marrow in this phase.
Inhibitors of the fusion of HIV to host cells, preventing viral entry. This includes compounds that block attachment of HIV ENVELOPE PROTEIN GP120 to CD4 RECEPTORS.
Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake.
Signal transducing adaptor proteins that contain SRC HOMOLOGY DOMAINS and play a role in CYTOSKELETON reorganization. c-crk protein is closely related to ONCOGENE PROTEIN V-CRK and includes several alternatively spliced isoforms.
RNA present in neoplastic tissue.
Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.
Genes whose expression is easily detectable and therefore used to study promoter activity at many positions in a target genome. In recombinant DNA technology, these genes may be attached to a promoter region of interest.
Process of generating a genetic MUTATION. It may occur spontaneously or be induced by MUTAGENS.
An ADP-ribosylating polypeptide produced by CORYNEBACTERIUM DIPHTHERIAE that causes the signs and symptoms of DIPHTHERIA. It can be broken into two unequal domains: the smaller, catalytic A domain is the lethal moiety and contains MONO(ADP-RIBOSE) TRANSFERASES which transfers ADP RIBOSE to PEPTIDE ELONGATION FACTOR 2 thereby inhibiting protein synthesis; and the larger B domain that is needed for entry into cells.
Sites on an antigen that interact with specific antibodies.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.
A malignant disease of the B-LYMPHOCYTES in the bone marrow and/or blood.
The most well known avian paramyxovirus in the genus AVULAVIRUS and the cause of a highly infectious pneumoencephalitis in fowl. It is also reported to cause CONJUNCTIVITIS in humans. Transmission is by droplet inhalation or ingestion of contaminated water or food.
A PROTEIN-TYROSINE KINASE family that was originally identified by homology to the Rous sarcoma virus ONCOGENE PROTEIN PP60(V-SRC). They interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways. Oncogenic forms of src-family kinases can occur through altered regulation or expression of the endogenous protein and by virally encoded src (v-src) genes.
Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.
A method (first developed by E.M. Southern) for detection of DNA that has been electrophoretically separated and immobilized by blotting on nitrocellulose or other type of paper or nylon membrane followed by hybridization with labeled NUCLEIC ACID PROBES.
Stem cells derived from HEMATOPOIETIC STEM CELLS. Derived from these myeloid progenitor cells are the MEGAKARYOCYTES; ERYTHROID CELLS; MYELOID CELLS; and some DENDRITIC CELLS.
Proteins produced from GENES that have mutated by the fusing of protein coding regions of more than one gene. Such hybrid proteins are responsible for some instances of ANTIBIOTIC RESISTANCE and defective biological processes such as NEOPLASMS.
A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.
A signal transducing adaptor protein that links extracellular signals to the MAP KINASE SIGNALING SYSTEM. Grb2 associates with activated EPIDERMAL GROWTH FACTOR RECEPTOR and PLATELET-DERIVED GROWTH FACTOR RECEPTORS via its SH2 DOMAIN. It also binds to and translocates the SON OF SEVENLESS PROTEINS through its SH3 DOMAINS to activate PROTO-ONCOGENE PROTEIN P21(RAS).
A protein present in the cell wall of most Staphylococcus aureus strains. The protein selectively binds to the Fc region of human normal and myeloma-derived IMMUNOGLOBULIN G. It elicits antibody activity and may cause hypersensitivity reactions due to histamine release; has also been used as cell surface antigen marker and in the clinical assessment of B lymphocyte function.
All of the processes involved in increasing CELL NUMBER including CELL DIVISION.
A ubiquitous hnRNP protein found in the CELL NUCLEUS and the CYTOPLASM. Translocations that result in the formation of fusion proteins containing parts of RNA-binding protein EWS may play a role in neoplastic processes such as EWING SARCOMA.
A cytologic technique for measuring the functional capacity of tumor stem cells by assaying their activity. It is used primarily for the in vitro testing of antineoplastic agents.
The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.
A light microscopic technique in which only a small spot is illuminated and observed at a time. An image is constructed through point-by-point scanning of the field in this manner. Light sources may be conventional or laser, and fluorescence or transmitted observations are possible.
A tricyclo bridged hydrocarbon.
Amino acid sequences found in transported proteins that selectively guide the distribution of the proteins to specific cellular compartments.
Biologically functional sequences of DNA chemically synthesized in vitro.
Proteins obtained from the species SACCHAROMYCES CEREVISIAE. The function of specific proteins from this organism are the subject of intense scientific interest and have been used to derive basic understanding of the functioning similar proteins in higher eukaryotes.
The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells.
A human cell line established from a diffuse histiocytic lymphoma (HISTIOCYTIC LYMPHOMA, DIFFUSE) and displaying many monocytic characteristics. It serves as an in vitro model for MONOCYTE and MACROPHAGE differentiation.
The process by which two molecules of the same chemical composition form a condensation product or polymer.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in neoplastic tissue.
Phosphotransferases that catalyzes the conversion of 1-phosphatidylinositol to 1-phosphatidylinositol 3-phosphate. Many members of this enzyme class are involved in RECEPTOR MEDIATED SIGNAL TRANSDUCTION and regulation of vesicular transport with the cell. Phosphatidylinositol 3-Kinases have been classified both according to their substrate specificity and their mode of action within the cell.
A form of antibodies consisting only of the variable regions of the heavy and light chains (FV FRAGMENTS), connected by a small linker peptide. They are less immunogenic than complete immunoglobulin and thus have potential therapeutic use.
A type of IN SITU HYBRIDIZATION in which target sequences are stained with fluorescent dye so their location and size can be determined using fluorescence microscopy. This staining is sufficiently distinct that the hybridization signal can be seen both in metaphase spreads and in interphase nuclei.
The complex series of phenomena, occurring between the end of one CELL DIVISION and the end of the next, by which cellular material is duplicated and then divided between two daughter cells. The cell cycle includes INTERPHASE, which includes G0 PHASE; G1 PHASE; S PHASE; and G2 PHASE, and CELL DIVISION PHASE.
Processes that stimulate the GENETIC TRANSCRIPTION of a gene or set of genes.
Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.
The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments.
A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.
The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development.
Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a CONSERVED SEQUENCE which can be represented by a CONSENSUS SEQUENCE.
A CELL LINE derived from the kidney of the African green (vervet) monkey, (CERCOPITHECUS AETHIOPS) used primarily in virus replication studies and plaque assays.

Polarized distribution of Bcr-Abl in migrating myeloid cells and co-localization of Bcr-Abl and its target proteins. (1/1620)

Bcr-Abl plays a critical role in the pathogenesis of Philadelphia chromosome-positive leukemia. Although a large number of substrates and interacting proteins of Bcr-Abl have been identified, it remains unclear whether Bcr-Abl assembles multi-protein complexes and if it does where these complexes are within cells. We have investigated the localization of Bcr-Abl in 32D myeloid cells attached to the extracellular matrix. We have found that Bcr-Abl displays a polarized distribution, colocalizing with a subset of filamentous actin at trailing portions of migrating 32D cells, and localizes on the cortical F-actin and on vesicle-like structures in resting 32D cells. Deletion of the actin binding domain of Bcr-Abl (Bcr-AbI-AD) dramatically enhances the localization of Bcr-Abl on the vesicle-like structures. These distinct localization patterns of Bcr-Abl and Bcr-Abl-AD enabled us to examine the localization of Bcr-Abl substrate and interacting proteins in relation to Bcr-Abl. We found that a subset of biochemically defined target proteins of Bcr-Abl redistributed and co-localized with Bcr-Abl on F-actin and on vesicle-like structures. The co-localization of signaling proteins with Bcr-Abl at its sites of localization supports the idea that Bcr-Abl forms a multi-protein signaling complex, while the polarized distribution and vesicle-like localization of Bcr-Abl may play a role in leukemogenesis.  (+info)

Adhesion to fibronectin stimulates proliferation of wild-type and bcr/abl-transfected murine hematopoietic cells. (2/1620)

Cells of most tissues require adhesion to a surface to grow. However, for hematopoietic cells, both stimulation and inhibition of proliferation by adhesion to extracellular matrix components have been described. Furthermore, it has been suggested that progenitor cells from chronic myelogenous leukemia show decreased beta1 integrin-mediated adhesion to fibronectin, resulting in increased proliferation and abnormal trafficking. However, we show here that the chronic myelogenous leukemia-specific fusion protein p210bcr/abl stimulates the expression of alpha5beta1 integrins and induces adhesion to fibronectin when expressed in the myeloid cell line 32D. Moreover, proliferation of both p210bcr/abl-transfected 32D (32Dp210) cells and untransfected 32D cells is stimulated by immobilized fibronectin. Cell cycle analysis revealed that nonadherent 32D and 32Dp210 cells are arrested in late G1 or early S phase, whereas the adherent fractions continue cycling. Although both adherent and nonadherent p210bcr/abl-transfected and parental 32D cells express equal amounts of cyclin A, a protein necessary for cell cycle progression at the G1/S boundary, cyclin A complexes immunoprecipitated from 32D cells cultured on immobilized fibronectin were found to be catalytically inactive in nonadherent but not in adherent cells. In addition, as compared with untransfected 32D cells, cyclin A immunoprecipitates from 32Dp210 cells exhibited a greatly elevated kinase activity and remained partially active irrespective of the adhesion status. The lack of cyclin A/cyclin-dependent kinase (CDK) 2 activity in nonadherent 32D cells appeared to result from increased expression and cyclin A complex formation of the CDK inhibitor p27(Kip1). Taken together, our results indicate that adhesion stimulates cell cycle progression of hematopoietic cells by down-regulation of p27(Kip1), resulting in activation of cyclin A/CDK2 complexes and subsequent transition through the G1/S adhesion checkpoint.  (+info)

Presence of P210bcrabl is associated with decreased expression of a beta chemokine C10 gene in a P210bcrabl-positive myeloid leukemia cell line. (3/1620)

BACKGROUND: Chronic myelogenous leukemia (CML) is thought to start with the acquisition of the t(9;22) chromosomal translocation that codes for the P210bcrabl tyrosine-specific protein kinase. The CML cells exhibit anchorage-independent cell growth and genetic instability. After the initial phase, the cells acquire the phenotype of growth factor-independent growth. After the chronic phase, the disease evolves into the accelerated and blastic phases through the process of sequential random mutation. MATERIALS AND METHODS: To identify some of the genetic changes that contribute to the phenotype of blastic and accelerated phase cells, we used differential display PCR to compare levels of cDNA reverse transcripts of mRNA in 32Dc13 cells and 32Dc13 cells that were stably transfected with a bcrabl cDNA plasmid in a constitutively expressed transcription unit. These cells were designated 32Dc13P210bcrabl. For these studies, we used the 32D myeloid leukemia cell line, which depends on IL-3 for growth. RESULTS: Following introduction of the bcr-abl cDNA through transfection, the cell line became growth factor independent, mimicking the change in phenotype that occurs during the later phases of CML. These differential display screening assays detected altered levels of transcripts for 28 genes. Of interest to the biology of growth factor-independent growth in the bcrabl-positive 32D cells was the fact that the C10 beta chemokine gene was expressed at higher levels in the 32Dc13 cells than in the 32Dc13P210bcrabl cells. CONCLUSIONS: These studies show that a C10 beta chemokine gene was expressed at different levels with or without P210bcrabl.  (+info)

Constitutive activation of the JAK2/STAT5 signal transduction pathway correlates with growth factor independence of megakaryocytic leukemic cell lines. (4/1620)

The factor-independent Dami/HEL and Meg-01 and factor-dependent Mo7e leukemic cell lines were used as models to investigate JAK/STAT signal transduction pathways in leukemic cell proliferation. Although Dami/HEL and Meg-01 cell proliferation in vitro was independent of and unresponsive to exogenous cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), IL-6, thrombopoietin (TPO), and tumor necrosis factor-alpha (TNF-alpha), the growth of Mo7e cells was dependent on hematopoietic growth factors. When these cell lines were cultured in medium without cytokines, a constitutively activated STAT-like DNA-binding factor was detected in nuclear extracts from both Dami/HEL and Meg-01 cells. However, the STAT-like factor was not detectable in untreated Mo7e cells, but was activated transiently in Mo7e cells in response to cytokine treatments. The constitutively activated and cytokine-induced STAT-like DNA-binding factor in these three cell lines was identified as STAT5 by oligonucleotide competition gel mobility assays and by specific anti-STAT antibody gel supershift assays. Constitutive activation of JAK2 also was detected in the factor-independent cell lines, but not in Mo7e cells without cytokine exposure. Meg-01 cells express a p185 BCR/ABL oncogene, which may be responsible for the constitutive activation of STAT5. Dami/HEL cells do not express the BCR/ABL oncogene, but increased constitutive phosphorylation of Raf-1 oncoprotein was detected. In cytokine bioassays using growth factor-dependent Mo7e and TF-1 cells as targets, conditioned media from Dami/HEL and Meg-01 cells did not show stimulatory effects on cell proliferation. Our results indicate that the constitutive activation of JAK2/STAT5 correlates with the factor-independent growth of Dami/HEL and Meg-01 cells. The constitutive activation of JAK2/STAT5 in Dami/HEL cells is triggered by a mechanism other than autocrine cytokines or the BCR/ABL oncoprotein.  (+info)

Extremely high and specific activity of DNA enzymes in cells with a Philadelphia chromosome. (5/1620)

BACKGROUND: Chronic myelogenous leukemia (CML) results from chromosome 22 translocations (the Philadelphia chromosome) that creates BCR-ABL fusion genes, which encode two abnormal mRNAs (b3a2 and b2a2). Various attempts to design antisense oligonucleotides that specifically cleave abnormal L6 BCR-ABL fusion mRNA have not been successful. Because b2a2 mRNA cannot be effectively cleaved by hammerhead ribozymes near the BCR-ABL junction, it has proved very difficult to engineer specific cleavage of this chimeric mRNA. Nonspecific effects associated with using antisense molecules make the use of such antisense molecules questionable. RESULTS: The usefulness of DNA enzymes in specifically suppressing expression of L6 BCR-ABL mRNA in mammalian cells is demonstrated. Although the efficacy of DNA enzymes with natural linkages decreased 12 hours after transfection, partially modified DNA enzymes, with either phosphorothioate or 2'-O-methyl groups at both their 5' and 3' ends, remained active for much longer times in mammalian cells. Moreover, the DNA enzyme with only 2'-O-methyl modifications was also highly specific for abnormal mRNA. CONCLUSIONS: DNA enzymes with 2'-O-methyl modifications are potentially useful as gene-inactivating agents in the treatment of diseases such as CML. In contrast to conventional antisense DNAs, some of the DNA enzymes used in this study were highly specific and cleaved only abnormal BCR-ABL mRNA.  (+info)

The presence of the Rb c-box peptide in the cytoplasm inhibits p210bcr-abl transforming function. (6/1620)

In order to test if the carboxyl terminal polypeptide of the Retinoblastoma (Rb) tumor suppressor protein, could be used to suppress the growth factor-independent growth phenotype of p210bcr-abl positive myeloid cells, we introduced a truncated form of the 3' end of the Rb cDNA encoding its last 173 amino acid residues (Rb C-box) which localize into the cytoplasm where the p210bcr-abl transforming protein is found, into myeloid cells (32D) which depends on the p210bcr-abl protein for IL3 growth factor-independent growth (32D-p210). The expression of the plasmid vectors carrying the Rb C-box cDNAs was shown to inhibit the abl tyrosine specific protein kinase activity of the p210(bcr-abl) oncoprotein and to suppress the IL3-independent growth phenotype of the 32D-p210 cells. The Rb C-box polypeptides did not suppress the growth of the untransfected 32D parental cell line in methylcellulose in the presence of IL3-conditioned medium. These results suggest that the cytoplasmic localization of the p210(bcr-abl) allows it to escape the effect of intranuclear proteins such as Rb which negatively regulate the p145(c-abl) kinase.  (+info)

Effects of bryostatin-1 on chronic myeloid leukaemia-derived haematopoietic progenitors. (7/1620)

Bryostatin-1 belongs to the family of macrocyclic lactones isolated from the marine bryozoan Bugula neritina and is a potent activator of protein kinase C (PKC). Bryostatin has been demonstrated to possess both in vivo and in vitro anti-leukaemic potential. In samples derived from chronic myeloid leukaemia (CML) patients, it has been demonstrated that bryostatin-1 induces a macrophage differentiation, suppresses colony growth in vitro and promotes cytokine secretion from accessory cells. We investigated the effect of bryostatin-1 treatment on colony-forming unit-granulocyte macrophage (CFU-GM) capacity in the presence of accessory cells, using mononuclear cells, as well as in the absence of accessory cells using purified CD34-positive cells. Cells were obtained from 14 CML patients as well as from nine controls. Moreover, CD34-positive cells derived from CML samples and controls were analysed for stem cell frequency and ability using the long-term culture initiating cell (LTCIC) assay at limiting dilution. Individual colonies derived from both the CFU-GM and LTCIC assays were analysed for the presence of the bcr-abl gene with fluorescence in situ hybridization (FISH) to evaluate inhibition of malignant colony growth. The results show that at the CFU-GM level bryostatin-1 treatment resulted in only a 1.4-fold higher reduction of CML colony growth as compared to the control samples, both in the presence and in the absence of accessory cells. However, at the LTCIC level a sixfold higher reduction of CML growth was observed as compared to the control samples. Analysis of the LTCICs at limiting dilution indicates that this purging effect is caused by a decrease in output per malignant LTCIC combined with an increase in the normal stem cell frequency. It is concluded that bryostatin-1 selectively inhibits CML growth at the LTCIC level and should be explored as a purging modality in CML.  (+info)

A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells. (8/1620)

Because of the probable causal relationship between constitutive p210(bcr/abl) protein tyrosine kinase activity and manifestations of chronic-phase chronic myelogenous leukemia (CML; myeloid expansion), a key goal is to identify relevant p210 substrates in primary chronic-phase CML hematopoietic progenitor cells. We describe here the purification and mass spectrometric identification of a 155-kD tyrosine phosphorylated protein associated with src homologous and collagen gene (SHC) from p210(bcr/abl)-expressing hematopoietic cells as SHIP2, a recently reported, unique SH2-domain-containing protein closely related to phosphatidylinositol polyphosphate 5-phosphatase SHIP. In addition to an N-terminal SH2 domain and a central catalytic region, SHIP2 (like SHIP1) possesses both potential PTB(NPXY) and SH3 domain (PXXP) binding motifs. Thus, two unique 5-ptases with striking structural homology are coexpressed in hematopoietic progenitor cells. Stimulation of human hematopoietic growth factor responsive cell lines with stem cell factor (SCF), interleukin-3 (IL-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF) demonstrate the rapid tyrosine phosphorylation of SHIP2 and its resulting association with SHC. This finding suggests that SHIP2, like that reported for SHIP1 previously, is linked to downstream signaling events after activation of hematopoietic growth factor receptors. However, using antibodies specific to these two proteins, we demonstrate that, whereas SHIP1 and SHIP2 selectively hydrolyze PtdIns(3,4,5)P3 in vitro, only SHIP1 hydrolyzes soluble Ins(1,3,4,5)P4. Such an enzymatic difference raises the possibility that SHIP1 and SHIP2 may serve different functions. Preliminary binding studies using lysates from p210(bcr/abl)-expressing cells indicate that both Ptyr SHIP2 and Ptyr SHIP1 bind to the PTB domain of SHC but not to its SH2 domain. Interestingly, SHIP2 was found to selectively bind to the SH3 domain of ABL, whereas SHIP1 selectively binds to the SH3 domain of Src. Furthermore, in contrast to SHIP1, SHIP2 did not bind to either the N-terminal or C-terminal SH3 domains of GRB2. These observations suggest (1) that SHIP1 and SHIP2 may have a different hierarchy of binding SH3 containing proteins and therefore may modulate different signaling pathways and/or localize to different cellular compartments and (2) that they may be substrates for tyrosine phosphorylation by different tyrosine kinases. Because recent evidence has clearly implicated both PI(3,4, 5)P3 and PI(3,4)P2 in growth factor-mediated signaling, our finding that both SHIP1 and SHIP2 are constitutively tyrosine phosphorylated in CML primary hematopoietic progenitor cells may thus have important implications in p210(bcr/abl)-mediated myeloid expansion.  (+info)

The Philadelphia chromosome (Ph1) is a translocation between chromosomes 9 and 22 that is found in chronic myelogenous leukemia (CML) and a subset of acute lymphocytic leukemia patients (ALL). In CML, this results in the expression of a chimeric 8.5-kilobase BCR-ABL transcript that encodes the P210BCR-ABL tyrosine kinase. The Ph1 chromosome in ALL expresses a distinct ABL-derived 7-kilobase messenger RNA that encodes the P185ALL-ABL protein. Since the expression of different oncogene products may play a role in the distinctive presentation of Ph1-positive ALL versus CML, it is necessary to understand the molecular basis for the expression of P185ALL-ABL. Both P210BCR-ABL and P185ALL-ABL are recognized by an antiserum directed to BCR determinants in the amino-terminal region of both proteins. Antisera to BCR determinants proximal to the BCR-ABL junction in CML immunoprecipitated P210BCR-ABL but not P185ALL-ABL. Nucleotide sequence analysis of complementary DNA clones made from RNA from the ...
The (9;22) translocation which produces the Philadelphia (Ph1) chromosome activates the abl oncogene from chromosome 9 by recombination with the bcr gene from chromosome 22. This fusion gene is transcribed into a new 8.5-kilobase chimeric mRNA which is translated into a novel Mr 210,000 fusion protein which has a protein tyrosine kinase activity that is greatly increased in comparison to the activity of the normal abl protein. Studies from this laboratory and others have shown that virtually all patients with chronic myelogenous leukemia have this new bcr/abl fusion gene. In contrast to these findings in chronic myelogenous leukemia, a small number of patients with Ph1(+) acute lymphoblastic leukemia (ALL) have been studied and were found to lack the bcr/abl fusion gene [bcr(-)], but to have a new activation of abl, by recombination with an as yet undetermined region on chromosome 22. In this study, nine adults with Ph1(+)-ALL have been examined for evidence of a bcr/abl fusion gene. Of the nine ...
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.. ...
The t(9;22)(q34;q11) chromosomal translocation is the most frequent cytogenetic abnormality found in human leukemias where it can be detected in ∼95% of patients with chronic myelogenous leukemia (CML) and in 30% to 40% of pre-B and acute lymphoblastic leukemia (1-3). This translocation results in the fusion of the BCR and ABL genes, leading to the expression of a BCR-ABL fusion protein with constitutively active ABL tyrosine kinase activity (1, 4). BCR-ABL-induced signaling is known to activate Ras-dependent signaling, phosphatidylinositol-3-kinase/Akt, and the Jak/STAT pathway (5). Additionally, BCR-ABL activates the transcription factor nuclear factor-κB (NF-κB) at least partly in a manner dependent on Ras (6). Suppression of NF-κB activation by expression of the so-called superrepressor form of IκBα blocked BCR-ABL-dependent xenograft tumor formation (6). Others (7) have also observed that NF-κB is activated by BCR-ABL in manner dependent on Ras. Furthermore, that study reported ...
ABL1 gene translocations can be seen in precursor T-acute lymphoblastic leukemia (T-ALL). The typical translocation partner is the NUP214 gene. BCR-ABL translocations are relatively rare in this entity. Furthermore, while there have been unique patterns of amplification noted among the NUP214-ABL fusion genes, there have been few such reports among cases with BCR-ABL fusion genes. Here we report a unique case of a 44-year old patient with T-ALL in which the blasts demonstrated a derivative chromosome 9 involving a 9;22 translocation and a dicentric Philadelphia chromosome 22 with a homogeneously staining region at the interface of the 9;22 translocation, leading to BCR-ABL1 gene amplification. Fluorescence in-situ hybridization (FISH) showed abnormal BCR/ABL1 fusions with the BCR-ABL1 gene amplification in 48% of the interphase cells analyzed. The translocation was confirmed by SNP array. We present a novel derivative chromosome 9 that shows BCR-ABL gene fusion along with a dicentric Philadelphia
p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.,/p> ,p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.,/p> ,p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).,/p> ,p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x,sup>64,/sup> + x,sup>4,/sup> + x,sup>3,/sup> + x + 1. The algorithm is described in the ISO 3309 standard. ,/p> ,p class=publication>Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.,br /> ,strong>Cyclic redundancy and other checksums,/strong>,br /> ,a href=>Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993),/a>),/p> Checksum:i ...
Background Tyrosine kinase inhibitors (TKIs) have demonstrated success in the treatment of acute lymphoblastic leukemia (ALL) in patients that express BCR-ABL rearrangements (Philadelphia chromosome [Ph]). The current study aimed to assess the efficacy of TKIs and prognostic factors in the treatment of adults with Ph+-ALL. Methods In this multicenter retrospective study, the relationship between Ph+-ALL and treatment outcomes among Chinese patients receiving TKI-containing induction/consolidation chemotherapy was examined. A total of 86 Ph+-ALL patients were included and followed for 3.85 (0.43-9.30) years. Overall survival (OS) and event-free survival (EFS) were analyzed. Results A total of 86 Ph+-ALL patients (40 females and 46 males; median age: 34.0 years) were enrolled, including those with BCR/ABL transcripts 190 (n = 52), 210 (n = 25), and 230 (n = 2); BCR/ABL isoform determination was not available for 7 patients. Mortality was influenced
Mice. To generate the double-transgenic Scl/Tal1-tTA × BCR/ABL strain (2), SCL-tTA mice (strain no. 017722) and TRE-BCR/ABL mice (strain no. 006202) were obtained from the Jackson Laboratory. Doxycycline hyclate (Sigma-Aldrich) was administered in the drinking water at a concentration of 0.2 mg/mL to mating mice and newborn pups to suppress BCR/ABL expression. At 4 weeks of age, doxycycline was withdrawn to induce BCR/ABL expression in some mice. As previously described, embryos from mice bearing a constitutive deletion of Ptn (61) were obtained from the RIKEN Institute by the Jackson Laboratory and rederived in a C57BL/6 background. The Scl/Tal1-tTA and TRE-BCR/ABL mice were backcrossed 8 generations into the PTN-/- strain. As a result, all experimental mice described were in a C57BL/6 background. Sperm from PTN-GFP mice (Tg[Ptn-EGFP]HJ32Gsat MGI no. 4847351) developed as part of the GENSAT Project Rockefeller University was obtained from the MMRRC Repository and the strain was rederived in a ...
Mice. To generate the double-transgenic Scl/Tal1-tTA × BCR/ABL strain (2), SCL-tTA mice (strain no. 017722) and TRE-BCR/ABL mice (strain no. 006202) were obtained from the Jackson Laboratory. Doxycycline hyclate (Sigma-Aldrich) was administered in the drinking water at a concentration of 0.2 mg/mL to mating mice and newborn pups to suppress BCR/ABL expression. At 4 weeks of age, doxycycline was withdrawn to induce BCR/ABL expression in some mice. As previously described, embryos from mice bearing a constitutive deletion of Ptn (61) were obtained from the RIKEN Institute by the Jackson Laboratory and rederived in a C57BL/6 background. The Scl/Tal1-tTA and TRE-BCR/ABL mice were backcrossed 8 generations into the PTN-/- strain. As a result, all experimental mice described were in a C57BL/6 background. Sperm from PTN-GFP mice (Tg[Ptn-EGFP]HJ32Gsat MGI no. 4847351) developed as part of the GENSAT Project Rockefeller University was obtained from the MMRRC Repository and the strain was rederived in a ...
Currently available medicines in the BCR-ABL TKIs class of drugs include Gleevec and Iclusig, as well as Tasigna, Bosulif, and Sprycel.. These BCR-ABL tyrosine kinase inhibitors (TKIs) are used for the treatment of specific types of blood cancers, including Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL), and less commonly, other types of cancers.. In May 2016 Health Canada issued a safety warning, BCR-ABL Tyrosine Kinase Inhibitors [GLEEVEC (imatinib mesylate), TASIGNA (nilotinib), BOSULIF (bosutinib), SPRYCEL (dasatinib), ICLUSIG (ponatinib hydrochloride)] - Risk of Hepatitis B Reactivation, which did not receive much public attention in the US.. From that May 2016 Health Canada document, we get the following detailed safety information about these drugs:. ...
Leukemias expressing constitutively activated mutants of ABL1 tyrosine kinase (BCR-ABL1, TEL-ABL1, NUP214-ABL1) usually contain at least 1 normal ABL1 allele. Because oncogenic and normal ABL1 kinases may exert opposite effects on cell behavior, we examined the role of normal ABL1 in leukemias induced by oncogenic ABL1 kinases. BCR-ABL1-Abl1(-/-) cells generated highly aggressive chronic myeloid leukemia (CML)-blast phase-like disease in mice compared with less malignant CML-chronic phase-like disease from BCR-ABL1-Abl1(+/+) cells. Additionally, loss of ABL1 stimulated proliferation and expansion of BCR-ABL1 murine leukemia stem cells, arrested myeloid differentiation, inhibited genotoxic stress-induced apoptosis, and facilitated accumulation of chromosomal aberrations. Conversely, allosteric stimulation of ABL1 kinase activity enhanced the antileukemia effect of ABL1 tyrosine kinase inhibitors (imatinib and ponatinib) in human and murine leukemias expressing BCR-ABL1, TEL-ABL1, and NUP214-ABL1.
Chronic myelogenous leukemia (CML) is a malignant hematopoietic stem cell disorder that is invariably associated with the expression of the p210 Bcr-Abl fusion protein. Although the deregulated, Abl-encoded tyrosine kinase activity is essential for disease progression, several studies have shown that Bcr encoded sequences are also necessary for p210 Bcr-Abl-mediated leukemogenesis. We have identified a non-classical ubiquitin binding domain (UBD) within the NH2-terminal Bcr sequences of p210 Bcr-Abl. Deletion of the UBD (p210 Bcr-Abl(ΔUBD)) does not impair the auto-or trans-kinase activity of p210 Bcr-Abl, nor does it impair the ability of p210 Bcr-Abl to interact with Grb2 and activate Erk1/2 signaling. Although β-catenin has been previously identified as a binding partner for Bcr and Bcr-Abl, p210 Bcr-Abl(ΔUBD) does not interact with β-catenin. Treatment with an E1 inhibitor impairs the interaction between β-catenin and p210 Bcr-Abl, suggesting that the interaction is ubiquitin-dependent. ...
Request Service. Chronic Myelogenous Leukemia (CML) and Acute Lymphocytic Leukemia (ALL). This is a test aimed at detecting and monitoring minimal residual disease in CML and ALL. This assay detects and quantitates cells that express the bcr-abl fusion transcripts resulting from either the major (p210) or minor (p190) breakpoints originating from the t(9;22) chromosomal translocation.This is a real-time TaqMan PCR assay, which expresses a patients results as a bcr-abl to abl ratio. Although this test can be used to diagnose CML and ALL, its best value is to follow bcr-abl/abl ratios in patients undergoing pharmacological therapy.. JAK2. PML-RARA. ...
Dormant leukemia stem cells (LSC) promote therapeutic resistance and leukemic progression as a result of unbridled activation of stem cell gene expression programs. Thus, we hypothesized that 1) deregulation of the hedgehog (Hh) stem cell self-renewal and cell cycle regulatory pathway would promote dormant human LSC generation and 2) that PF-04449913, a clinical antagonist of the GLI2 transcriptional activator, smoothened (SMO), would enhance dormant human LSC eradication. To test these postulates, whole transcriptome RNA sequencing (RNA-seq), microarray, qRT-PCR, stromal co-culture, confocal fluorescence microscopic, nanoproteomic, serial transplantation and cell cycle analyses were performed on FACS purified normal, chronic phase (CP) chronic myeloid leukemia (CML), blast crisis (BC) phase CML progenitors with or without PF-04449913 treatment. Notably, RNA-seq analyses revealed that Hh pathway and cell cycle regulatory gene overexpression correlated with leukemic progression. While lentivirally
Leukemias are diseases characterized by an uncontrolled proliferation of malignant hematopoietic stem cells. The fusion gene BCR-ABL is the result of a reciprocal translocation between chromosome 9 and chromosome 22 t (9;22) and encodes an oncogenic tyrosine kinase protein responsible for the neoplastic transformation observed in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The isoform p210 is the hallmark of CML, detectable in more than 95% of cases, while in LAL, the fusion gene BCR-ABL may be present in both isoforms p190 (60% of cases) and p210 (40 % of cases). The molecular detection of BCR-ABL is essential to diagnose CML and Philadelphia positive ALL, making possible the administration of proper treatment. Moreover, the discrimination of the isoform, only possible using molecular methods, facilitates the choice of the specific quantitative test for the molecular monitoring during the treatment. To date, the most widely used molecular techniques for the detection ...
TY - JOUR. T1 - Genomic mechanisms of p210BCR-ABL signaling. T2 - Induction of heat shock protein 70 through the GATA response element confers resistance to paclitaxel-induced apoptosis. AU - Ray, Sutapa. AU - Lu, Ying. AU - Kaufmann, Scott H.. AU - Gustafson, W. Clay. AU - Karp, Judith E.. AU - Boldogh, Istvan. AU - Fields, Alan P.. AU - Brasier, Allan R.. PY - 2004/8/20. Y1 - 2004/8/20. N2 - Chronic myelogenous leukemia (CML) results from a t(9,22) translocation, producing the p210BCR-ABL oncoprotein, a tyrosine kinase that causes transformation and chemotherapy resistance. To further understand mechanisms mediating chemotherapy resistance, we identified 556 differentially regulated genes in HL-60 cells stably expressing p210BCR-ABL versus those expressing an empty vector using cDNA macro- and oligonucleotide microarrays. These BCR-ABL-regulated gene products play diverse roles in cellular function including apoptosis, cell cycle regulation, intracellular signaling, transcription, and cellular ...
The break on chromosome 9 involves a gene called Abl and the break on chromosome 22 involves a gene called Bcr. The Bcr and Abl genes combine to make the CML causing gene called the Bcr-Abl gene. There doesnt seem to be any rhyme or reason as to why this occurs; it just does. This Bcr-Abl gene produces a dysfunctional protein called BCR-ABL tyrosine kinase; this leads to the abnormal regulation of cell growth and survival and is responsible for CML. Think of it as a faucet that is constantly in the on position. It is on and making immature white cells that are crowding out the good white cells as well as the red cells and platelets. ...
Chronic myeloid leukemia (CML) results from hematopoietic stem cell transformation by the BCR-ABL kinase. Despite the success of BCR-ABL tyrosine kinase inhibitors (TKIs) in treating CML patients, leukemia stem cells (LSCs) resist elimination and persist as a major barrier to cure. Previous studies suggest that overexpression of the sirtuin 1 (SIRT1) deacetylase may contribute to LSC maintenance in CML. Here, by genetically deleting SIRT1 in transgenic CML mice, we definitively demonstrated an important role for SIRT1 in leukemia development. We identified a previously unrecognized role for SIRT1 in mediating increased mitochondrial oxidative phosphorylation in CML LSCs. We showed that mitochondrial alterations were kinase independent and that TKI treatment enhanced inhibition of CML hematopoiesis in SIRT1-deleted mice. We further showed that the SIRT1 substrate PGC-1α contributed to increased oxidative phosphorylation and TKI resistance in CML LSCs. These results reveal an important role for ...
We used specific antisera and immunohistochemical methods to investigate the subcellular localization and expression of Bcr, Abl, and Bcr-Abl proteins in leukemic cell lines and in fresh human leukemic and normal samples at various stages of myeloid differentiation. Earlier studies of the subcellula …
Overcoming drug resistance and eradicating cancer stem cells to overcome MRD remain major challenges in the treatment of BCR-ABL+ human leukemia and other cancers. Here, we provide preclinical evidence that a combination of TKI and PP2A inhibitors is an improved strategy to target drug-insensitive stem/progenitor cells. Although PP2A functions as a tumor suppressor in several types of cancer (52, 53), we demonstrated a prosurvival role for PP2A in TKI-insensitive leukemic stem/progenitor cells. PP2A is an important regulator of G2-M checkpoint entry, dephosphorylating CDK1 substrates that facilitate mitotic exit (37, 54); thus, PP2A inhibitors force premature cell cycle entry. This works synergistically with DNA-damaging agents, such as DNA-alkylating agents or ionizing radiation, to increase tumor killing in several cancer models (33, 34, 55). When we tested the effects of the PP2A inhibitors LB100/LB102 on CML cells, we observed an expected increase in G2-M fraction and mitotic catastrophe, ...
Bosutinib is a synthetic quinolone derivative and dual kinase inhibitor that targets both Abl and Src kinases with potential antineoplastic activity. Unlike imatinib, bosutinib inhibits the autophosphorylation of both Abl and Src kinases, resulting in inhibition of cell growth and apoptosis. Because of the dual mechanism of action, this agent may have activity in resistant CML disease, other myeloid malignancies and solid tumors. Abl kinase is upregulated in the presence of the abnormal Bcr-abl fusion protein which is commonly associated with chronic myeloid leukemia (CML). Overexpression of specific Src kinases is also associated with the imatinib-resistant CML phenotype.
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TY - JOUR. T1 - Sensitivity of SNX2-ABL1 toward tyrosine kinase inhibitors distinct from that of BCR-ABL1. AU - Tomita, Osamu. AU - Iijima, Kazutoshi. AU - Ishibashi, Takeshi. AU - Osumi, Tomoo. AU - Kobayashi, Kenichiro. AU - Okita, Hajime. AU - Saito, Masahiro. AU - Mori, Tetsuya. AU - Shimizu, Toshiaki. AU - Kiyokawa, Nobutaka. PY - 2014/3/1. Y1 - 2014/3/1. N2 - We introduced SNX2-ABL1, a novel ABL1-related chimeric transcript lacks SH3 and SH2 domains, into murine Ba/F3 cells and compared their function with that of BCR-ABL1. After the expression of SNX2-ABL1 proteins, Ba/F3 cells acquired an ability to proliferate in an IL-3-independent manner. Upon treatment with both imatinib and dasatinib, BCR-ABL1-expressing Ba/F3 cells underwent rapid apoptosis, whereas SNX2-ABL1-expressing Ba/F3 cells showed poorer sensitivity toward these TKIs and could proliferate in the presence of a low dose of dasatinib. Therefore, other TKIs with a more selective effect against this chimeric kinase should be ...
The ABL proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Mutations in the ABL gene are associated with chronic myelogenous leukemia (CML), where it is activated by being translocated within the BCR (breakpoint cluster region) gene on chromosome 22. The BCR-ABL transcript encodes a tyrosine kinase, which activates mediators of the cell cycle regulation system, leading to a clonal myeloproliferative disorder. ABL exon 4 primer set have the function to enrich mutation type of ABL gene and allows to detect target codons M244 on DNA samples.. ...
The ABL proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Mutations in the ABL gene are associated with chronic myelogenous leukemia (CML), where it is activated by being translocated within the BCR (breakpoint cluster region) gene on chromosome 22. The BCR-ABL transcript encodes a tyrosine kinase, which activates mediators of the cell cycle regulation system, leading to a clonal myeloproliferative disorder. ABL exon 6 primer set have the function to enrich mutation type of ABL gene and allows to detect target codons T315 on DNA samples.. ...
BCR-ABL is a mutation that is formed by the combination of two genes, known as BCR and ABL. Its sometimes called a fusion gene. The BCR gene is normally on chromosome number 22. The ABL gene is normally on chromosome number 9. The BCR-ABL mutation happens when pieces of BCR and ABL genes break off and switch places ...
Ponatinib is a novel Bcr-Abl tyrosine kinase inhibitor that is especially effective against the T315I mutation for the treatment of chronic myeloid leukemia. FDA approved on December 14, 2012.
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Bcr-Abl is an oncogenic fusion protein which expression enhances tumorigenesis, and has been highly associated with chronic myeloid leukemia (CML). Acquired drug resistance in mutant Bcr-Abl has enhanced pathogenesis with the use of single therapy agents such as Nilotinib. Moreover, allosteric targeting has been identified to consequentially inhibit Bcr-Abl activity, which led to the recent development of ABL-001 (asciminib) that selectively binds the myristoyl pocket. Experimental studies have revealed that the combination of Nilotinib and ABL-001 induced a bent conformation in the C-terminal helix of Bcr-Abl; a benchmark of inhibition, thereby exhibiting a greater potency in the treatment of CML, surmounting the setbacks of drug resistance, disease regression and relapse ...
PD 180970 | Bcr-Abl inhibitor | PD180970 | CAS [287204-45-9] | Axon 1137 | Axon Ligand™ with >99% purity available from supplier Axon Medchem, prime source of life science reagents for your research
Flumatinib, also known as HHGV678, is a selective inhibitor of BCR-ABL/PDGFR/KIT. Flumatinib is currently in Phase I clinical trials in China for the treatment of chronic myelogenous leukemia (CML). Flumatinib effectively overcomes drug resistance of certain KIT mutants. Flumatinib mesylate can reduce the expression of C-MYC, HIF-1 α and VEGF in U266 cell line in a time- and dose-dependent manners.
Dr. Brian Druker and colleagues monitored white blood cell counts in six patients with chronic myeloid leukemia treated with the drug, STI571, which blocks the activity of the cancer-causing tyrosine kinase BCR-ABL. ...
Background A sensitive and standardized monitoring of deep molecular response (MR) based on BCR-ABL1 transcript level quantification is an essential part of CML tyrosine kinase inhibitor (TKI) stopping trials. Detailed laboratory recommendations, developed as a part of the European Treatment and Outcome Study (EUTOS) for CML, to enable testing laboratories to score MR in a reproducible manner...
Finding the right BCR-ABL1 tyrosine kinase inhibitor: a case report of successful treatment of a patient with chronic myeloid leukemia and a V299L mutation using nilotinib.
What is PCR?. PCR is short for polymerase chain reaction. It is the main type of test used in CML to measure your response to treatment. Its also used to test for other things, like viruses after a bone marrow transplant.. In CML, a PCR test is done in a lab, using a sample of your blood. The test finds the amount of genetic blueprints for the BCR-ABL gene that causes CML. A PCR test thus measures the residual (remaining) disease in your blood.. Why should you know your PCR?. Because your PCR number can be compared to the results from your earlier PCR tests, it helps give you an idea of how you are responding to treatment over time. Your doctor can explain how this number compares to where it should be, so its important to ask about it if you dont know it.. How often should I have the test?. Most experts recommend that you should have a PCR test performed every three months during the early stages of your treatment. Once your BCR-ABL levels have begun to drop, indicating a good response ...
Chan WW, Wise SC, Kaufman MD, Ahn YM, Ensinger CL, Haack T, Hood MM, Jones J, Lord JW, Lu WP, Miller D, Patt WC, Smith BD, Petillo PA, Rutkoski TJ, Telikepalli H, Vogeti L, Yao T, Chun L, Clark R, Evangelista P, Gavrilescu LC, Lazarides K, Zaleskas VM, Stewart LJ, Van Etten RA, Flynn DL. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell. 2011 Apr 12; 19(4):556-68 ...
The CE IVD real-time PCR kit is intended for a qualitative determination of a type of the BCR-ABL1 fusion gene alteration. Apart from commonly occurring fusions the kit detects rare alterations as well. Detection method based on one-step RT-qPCR ensures quick, less laborious and, above all, semiquantitative determination of the fusion type, while sophisticated system of controls ensures validity of the result and its adequate interpretation.. ...
Cytogenetic and FISH analysis of bone marrow showed that most patients had a decrease in the fraction of BCR-ABL-or Philadelphia-positive cells, though typically marrow remained positive, often in a fairly high percentage of cells. Eventually some values fell within the normal range. If we look with RT-PCR, which is more sensitive, Dr. Peterson says, many were still positive for BCR-ABL. Patients who remained positive for BCR-ABL later progressed; some developed accelerated phase or blast crisis. So we dont know that imatinib can cure CML, Dr. Peterson says. That is our hope. And we see such good responses that we think survival will be lengthened. But we dont yet know that clearly. However, she adds, this study was done in pretreated patients. Similar studies in newly diagnosed patients ...
TY - JOUR. T1 - Growth inhibition of chronic myelogenous leukemia cells by ODN-1, an aptameric inhibitor of p210(bcr-abl) tyrosine kinase activity. AU - Schwartz, Gretchen N.. AU - Liu, Yue Qin. AU - Tisdale, John. AU - Walshe, Kate. AU - Fowler, Daniel. AU - Gress, Ronald. AU - Bergan, Raymond C.. PY - 1998/1/1. Y1 - 1998/1/1. N2 - p210(bcr-abl)-Related tyrosine kinase activity has been shown to cause chronic myelogenous leukemia (CML), a disease of bone marrow stem cells. Having previously demonstrated that the aptameric oligonucleotide, ODN-1, could inhibit p210(bcr-abl) kinase activity, the current study sought to determine if ODN-1 could selectively inhibit the growth of CML cells relative to that of normal bone marrow. ODN-1, when introduced by electroporation into peripheral blood mononuclear cells (PBMC) from patients with CML, decreased the number of committed progenitors (CML CFU-GM) by an average of 67% ± 19% (mean ± SEM, range 28-98%). Treatment of CML PBMC with ODN-1 was also ...
TY - JOUR. T1 - Nilotinib. T2 - A novel Bcr-Abl tyrosine kinase inhibitor for the treatment of leukemias. AU - Jabbour, Elias. AU - El Ahdab, Samih. AU - Cortes, Jorge. AU - Kantarjian, Hagop. PY - 2008/7/1. Y1 - 2008/7/1. N2 - The successful introduction of the tyrosine kinase inhibitors has initiated a new era in the management of chronic myeloid leukemia (CML). Imatinib mesilate therapy has significantly improved the prognosis of CML. A minority of patients in chronic-phase CML - and more patients in advanced phases - are resistant to imatinib, or develop resistance during treatment. This is attributed, in 40 - 50% of cases, to the development of mutations in the Bcr-Abl tyrosine kinase domain that impair imatinib binding. Nilotinib (Tasigna®) is a novel potent selective oral kinase inhibitor. Preclinical and clinical investigations demonstrate nilotinib effectively overcomes imatinib resistance, and has induced high rates of hematologic and cytogenetic responses in CML post imatinib ...
In this retrospective analysis, fourteen/18 (78%) evaluable patients were found challenged with higher doses of IM (600-800 mg/day), with one return to CP and one transient CCyR after IM combined with chemotherapy, and 12 failures. Six patients (1 CP, 5 BC) were treated with dasatinib, and no difference in survival was seen between dasatinib-treated and non-treated patients (p=0.15). None of the patients received nilotinib. Additionally, 3 patients underwent allogeneic stem cell transplantation with 2 remaining alive at 1 and 14 months follow-up. Finally, at latest follow-up, overall survival since IM initiation (Figure 1B), however longer for CP (42.5 Mo.) was not statistically different than that for AP+BC (17.5 Mo., p=0.08) patients.. The onset of BCR-ABLT315I mutations during the treatment of CML with TKIs remains challenging, because this mutation is the most frequently identified in IM-treated patients6, and none of the TKIs clinically available to date4,5,6 retain any activity in vitro. ...
The BCR-ABL1 oncoprotein is found in a subset of patients with ALL carrying the Philadelphia chromosome. This translocation is the most common cytogenetic abnormality in adults, with ALL occurring in 25% of patients (33). BCR-ABL1 defines a high-risk group and, as such, patients receive intensive chemotherapy in combination with ABL TKIs and are considered for hematopoietic stem cell transplantation (HSCT). Despite the great success with combination of high-dose ABL TKIs and intensive chemotherapy, there are still drawbacks that need to be addressed. Above all, 40% of patients, even with HSCT, have relapse of the disease. Furthermore, it is not clear whether responsive patients without HSCT cannot have relapse of the disease, as there is evidence that BCR-ABL1-positive leukemia stem cells remain present in the patients bone marrow even after years of therapy. Therefore, it is necessary to define targets in BCR-ABL1-positive leukemia stem cells that may be candidates for new treatment ...
Telomeres are specific nucleoprotein structures at the ends of eukaryotic chromosomes. Telomeres and telomere-associated proteins maintain genome stability by protecting the ends of chromosomes from fusion and degradation. In normal somatic cells, the length of the telomeres gradually becomes shortened with cell division. In tumor cells, the shortening of telomeres length is accelerated under the increased proliferation pressure. However, it will be maintained at an extremely short length as the result of activation of telomerase. Significantly shortened telomeres, activation of telomerase, and altered expression of telomere-associated proteins are common features of various hematologic malignancies and are related with progression or chemotherapy resistance in these diseases. In patients who have received hematopoietic stem cell transplantation (HSCT), the telomere length and the telomerase activity of the engrafted donor cells have a significant influence on HSCT outcomes. Transplantation-related
Chronic myelogenous leukemia (CML) is an uncommon type of cancer of the bone marrow - the spongy tissue inside bones where blood cells are made. CML causes an increased number of white blood cells in the blood.. The term chronic in chronic myelogenous leukemia indicates that this cancer tends to progress more slowly than acute forms of leukemia. The term myelogenous (my-uh-LOHJ-uh-nus) in chronic myelogenous leukemia refers to the type of cells affected by this cancer.. Chronic myelogenous leukemia can also be called chronic myeloid leukemia and chronic granulocytic leukemia. It typically affects older adults and rarely occurs in children, though it can occur at any age.. Advances in treatment have contributed to a greatly improved prognosis for people with chronic myelogenous leukemia. Most people will achieve remission and live for many years after diagnosis. ...
This study is characterizing the pharmacokinetics of vincristine using two different cohorts of patients. The first cohort includes patients with acute lymphoblastic leukemia (ALL) that are Bcr-Abl positive. This cohort of patients will receive vincristine along with imatinib in the induction chemotherapy regimen. The second cohort includes patients with ALL that are Bcr-Abl negative. This cohort of patients will receive vincristine without imatinib in the induction chemotherapy regimen. This study involves blood draws beginning on day 7 of the treatment protocol and these samples will be analyzed for pharmacokinetic parameters.. Imatinib and vincristine are both metabolized by the hepatic CYP 450 enzyme system. Imatinib is an inhibitor of the system and co-administration of imatinib and vincristine has the potential to increase the blood level of vincristine. This could explain the increased level of neurotoxicity that is currently being seen with the co-administration of these two agents in ...
Chronic myeloid leukemia (CML) is a malignancy of the pluripotent hematopoietic stem cell, in which a reciprocal translocation between chromosomes 9 and 22 produces BCR-ABL1, the oncogenic tyrosine kinase that drives disease (1). In newly diagnosed CML patients, tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 are remarkably effective at eliminating most BCR-ABL1-positive cells, especially in the chronic phase (CP-CML). However, TKIs do not eliminate CML leukemic stem cells (LSCs), and while some studies have reported treatment-free remission following deep molecular response, life-long therapy is required to maintain remission in most patients. Understanding the mechanisms driving TKI resistance will inform treatment strategies aimed at curing the disease.. TKI resistance is often linked to point mutations in the BCR-ABL1 kinase domain that impair drug binding. However, many cases of clinical resistance occur in the absence of BCR-ABL1 mutations (2). BCR-ABL1-independent resistance is a ...
0.000). Patients having highly positive value may grow some kinase domain mutations causing resistance to prescribed TKI and have evolved into accelerated (AP) or relapse phases (data not shown).. The patients who had achieved the complete cytogenetic response (CCYR) within first 6 months and currently still in CCYR and surviving were also analyzed. Those patients who had not achieved the cytogenetic remission within first 6 months did not show good prognosis. Some of them achieved complete response, but some of them were in AP phase. The BCR-ABL1 fusion protein assay showed considerable consistency with RQ-PCR and cytogenetic results. Studying molecular response groups (Table 6), we have found a distinct difference in MFI values such as complete molecular response (CMR) patients are also negative to be detected for BCR-ABL protein by fluorescence based flow cytometry assay (mean MFI 1.24). Mean MFI of mMR group, being 2.61, indicates clearly the difference in response levels.. The discrepancy ...
Mutations in the ABL1 gene are associated with chronic myelogenous leukemia (CML). In CML, the gene is activated by being translocated within the BCR (breakpoint cluster region) gene on chromosome 22. This new fusion gene, BCR-ABL, encodes an unregulated, cytoplasm-targeted tyrosine kinase that allows the cells to proliferate without being regulated by cytokines. This, in turn, allows the cell to become cancerous. This gene is a partner in a fusion gene with the BCR gene in the Philadelphia chromosome, a characteristic abnormality in chronic myelogenous leukemia (CML) and rarely in some other leukemia forms. The BCR-ABL transcript encodes a tyrosine kinase, which activates mediators of the cell cycle regulation system, leading to a clonal myeloproliferative disorder. The BCR-ABL protein can be inhibited by various small molecules. One such inhibitor is imatinib mesylate, which occupies the tyrosine kinase domain and inhibits BCR-ABLs influence on the cell cycle. Second generation BCR-ABL ...
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell. The natural history of CML has a triphasic clinical course comprising of an initial chronic phase (CP), which is characterized by expansion of functionally normal myeloid cells, followed by an accelerated phase (AP) and finally a more aggressive blast phase (BP), with loss of terminal differentiation capacity. On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22. The BCR/ABL fusion gene encodes p210 BCR/ABL, an oncoprotein, which, unlike the normal p145 c-Abl, has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. While fusion of c-ABL and BCR is believed to be the primary cause of the ...
Background Cystatin F is really a proteins inhibitor of cysteine peptidases, portrayed in immune cells and localised in endosomal/lysosomal compartments predominantly. High-104 cell series were set up, either by treatment by ionomycin or by immunosuppressive changing growth aspect beta. Decreased cytotoxicity correlated with an increase of degrees of cystatin F with attenuated actions of cathepsins C, L and H and of granzyme B. Co-localisation of cystatin cathepsins and F C, L and H and connections between cystatin F and cathepsins C and H were demonstrated. Conclusions Cystatin F is definitely designated as a possible regulator of T cell cytotoxicity, similar to its part in natural killer cells. (BioGenes GmbH, Berlin, Germany), as a negative control. Dynabeads protein G with bound antibodies was then added to lysates. After rotation at 4C over night, beads were washed three times with lysis buffer and boiled for 10 minutes in 1 SDS loading buffer. Eluted proteins were analysed by western blot. ...
Supplementary MaterialsSupplementary Table 1 Nutrient requirements. were divided into 2 groups: glutamine group (N=44) and non-glutamine group (N=47). We analyzed the rate of weight change, infection (clinically/microbiologically documented), complications (duration of mucositis and neutropenia, acute graft versus host disease), and 100-days mortality in each group. Results Regarding the clinical characteristics from the individuals, there have been no significant variations between your 2 organizations except that there is a larger percentage of myeloablative fitness routine in the glutamine group ( em P /em =0.005). In the glutamine group, the common amount of times of glutamine make use of, parenteral nourishment, and mucositis was 7.61.4, 14.69.9, and 13.39.5, respectively. Furthermore, multivariate evaluation revealed chances ratios of 0.37 (95% CI, 0.14C0.96; em P /em =0.042) and 0.08 (95% CI, 0.01C0.98; em P /em =0.048) for clinically documented disease and 100-days mortality, ...
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell. The natural history of CML has a triphasic clinical course comprising of an initial chronic phase (CP), which is characterized by expansion of functionally normal myeloid cells, followed by an accelerated phase (AP) and finally a more aggressive blast phase (BP), with loss of terminal differentiation capacity. On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22. The BCR/ABL fusion gene encodes p210 BCR/ABL, an oncoprotein, which, unlike the normal p145 c-Abl, has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. While fusion of c-ABL and BCR is believed to be the primary cause of the ...
Dr. Radich explored the clinical decision-making regarding the selection of therapies for CML and emphasized that response milestones as listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CML should guide the way. For upfront therapy, Dr. Radich noted that one could start with either imatinib or one of the newer agents, based on clinical features (such as the Sokal score), comorbities, and treatment goals. Regardless of the first agent used, it is important to give initial therapy a fair trial before considering it ineffective, he added.. The first milestone is the 3-month BCR-ABL/ABL percentage. According to the NCCN Guidelines, if the BCR-ABL/ABL is less than 10% (indicative of a lack of response), it may be time to consider a second-generation agent. However, the European LeukemiaNet (ELN) guidelines are a bit more patient: if the BCR-ABL/ABL is less than 10% at 6 months, they suggest considering a switch to another agent, noted Dr. Radich.. Frankly, there are ...
Chronic myeloid leukemia (CML) results from hematopoietic stem cell transformation by the BCR-ABL kinase. Despite the success of BCR-ABL tyrosine kinase inhibitors (TKIs) in treating CML patients, leukemia stem cells (LSCs) resist elimination and persist as a major barrier to cure. Previous studies suggest that overexpression of the sirtuin 1 (SIRT1) deacetylase may contribute to LSC maintenance in CML. Here, by genetically deleting SIRT1 in transgenic CML mice, we definitively demonstrated an important role for SIRT1 in leukemia development. We identified a previously unrecognized role for SIRT1 in mediating increased mitochondrial oxidative phosphorylation in CML LSCs. We showed that mitochondrial alterations were kinase independent and that TKI treatment enhanced inhibition of CML hematopoiesis in SIRT1-deleted mice. We further showed that the SIRT1 substrate PGC-1α contributed to increased oxidative phosphorylation and TKI resistance in CML LSCs. These results reveal an important role for ...
AMA : Kronik Miyeloid L semi (KML) klonal bir k k h cre hastal d r ve BCR-ABL f zyon geni ile ili kilidir. Hastal k tedavi edilmedi i zaman, kronik evreden h zlanm evreye ilerler ve sonunda akut l semi ile sonu lan r. L semik transformasyonda temel olarak gerekli olan ve klinik olarak ili kili onkoproteinlerin belirlenmesi spesifik anti-l semik ila lar i in yeni molek ler hedef olabilecekleri i in nemlidir. Bu al ma baz M s rl kronik evre KML hastalar nda HOXA9 gen sunum oran n belirlemede ve bunun BCR-ABL sunumu ile ili kisinin ve klinik neminin de erlendirilmesinde ba lang ad m d r ...
TY - JOUR. T1 - Probing of the secondary structure of maxizymes.. AU - Zhou, J. M.. AU - Nakamatsu, Y.. AU - Kuwabara, T.. AU - Warashina, M.. AU - Tanaka, Y.. AU - Yoshinari, K.. AU - Taira, K.. N1 - Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine. PY - 1999. Y1 - 1999. N2 - The protein encoded by chimeric BCR-ABL mRNA causes chronic myelogenous leukemia (CML). We showed previously that a novel allosterically controllable ribozyme, of the type known as a maxizyme, can cleave this mRNA, with high specificity and high-level activity in vivo. In order to probe the putative conformational changes, we used a weakly alkaline solution to hydrolyze differentially phosphodiester bonds that were located in different environments. As indicated by earlier data obtained in vivo, our results demonstrated that the active conformation was achieved only in the presence of the junction within the chimeric BCR-ABL mRNA.. AB - The protein encoded by ...
Hematology: Chronic myelogenous leukemia (cml) | Stem cell transplant. Treatment in Ulm, Germany ✈ Find the best medical programs at BookingHealth - ✔Compare the prices ✔Online booking.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disease which is distinguished by an increased number of mature and immature granulocytes in peripheral blood, bone marrow, with increased granulocytopoiesis and splenomegaly. The disease is defined by the presence of the BCR-ABL fusion gene. This anomaly is probably necessary and sufficient for the development of chronic myeloid leukemia. ...
Chronic Myeloid Leukemia (CML) is characterized by increased and unregulated growth of myeloid cells in the bone marrow and accumulation of these cells in the blood. Most CML is caused by a chromosomal abnormality that results in a fusion between Abl tyrosine kinase and BCR gene on chromosome 2, which results in a constitutively active tyrosine kinase. Most CMLs are treated with tyrosine kinase inhibitors (TKI) such as imatinib. Some forms of CML, however, are resistant to TKI treatment and proceed independent of BCR-Abl1 activity. A recent colloborative study utilizing Cellectas unique platform in paired imatinib-resistant and imatininb-sensitive K-562 CML cell lines to identify other genes whose knockdown might play a role in the survival of the imatinib-resistant cells. This loss-of-function shRNA library screen identified RAN and XPO1, which are components of the nucleocytoplasmic transport complex.. When these genes were knocked down and the cells were treated with imatinib, the cells were ...
Beginning with imatinib a decade ago, therapy based on targeted inhibition of the BCR-ABL kinase has greatly improved the prognosis for chronic myeloid leukemia (CML) patients. The recognition that some patients experience relapse due to resistance-conferring point mutations within BCR-ABL sparked the development of the second-generation ABL kinase inhibitors nilotinib and dasatinib. Collectively, these drugs target most resistant BCR-ABL mutants, with the exception of BCR-ABLT315I. A third wave of advances is now cresting in the form of ABL kinase inhibitors whose target profile encompasses BCR-ABLT315I. The leading third-generation clinical candidate for treatment-refractory CML, including patients with the T315I mutation, is ponatinib (AP24534), a pan-BCR-ABL inhibitor that has entered pivotal phase 2 testing. A second inhibitor with activity against the BCR-ABLT315I mutant, DCC-2036, is in phase 1 clinical evaluation. We provide an up-to-date synopsis of BCR-ABL signaling pathways, highlight ...
Imatinib mesylate is a small-molecule tyrosine kinase inhibitor that was initially developed as a 2-phenylaminopyrimidine derivative specific for PDGFR. Imatinib was subsequently found to be a potent inhibitor of ABL kinases, including the BCR-ABL fusion protein generated as a result of the t(9;22) chromosomal translocation (Philadelphia chromosome) found in chronic myelogenous leukemia (CML), and was…. ...
Chronic myelogenous leukemia treatments include tyrosine kinase inhibitors, high-dose therapy with allogeneic transplantation, and other medications. Get detailed information about chronic myelogenous leukemia (CML) treatment options in this summary for clinicians.
Dr. Liawaty Ho answered: CML: CML is associated with philadelphia chromosome that result in the abnormal bcr-abl fusion gene. This becomes the target of tr...
The exchange of genetic information that produces the Philadelphia chromosome brings together two genes: the BCR (breakpoint cluster region) gene on chromosome 22 and the ABL (Ableson leukemia virus) gene on chromosome 9. The combination of these two genes into the single BCR-ABL gene results in the production of a protein that contributes to uncontrolled cell growth.. Initially in CML, there is a gradual increase in mature, abnormal myeloid cells in the bone marrow. These cells eventually spill into the blood and other organs, causing symptoms such as fatigue from anemia or an enlarged spleen. The increase in leukemic cell numbers occurs slowly at first and is referred to as the chronic phase, but these cells invariably begin to increase more rapidly and/or include less mature cells, resulting in the accelerated or blastic phase. In order to understand the best treatment options available for chronic myeloid leukemia, it is important to know the phase of leukemia, since all new treatment ...
Free, official coding info for 2021 ICD-10-CM C92.11 - includes detailed rules, notes, synonyms, ICD-9-CM conversion, index and annotation crosswalks, DRG grouping and more.
Free, official coding info for 2018 ICD-10-CM C92.10 - includes detailed rules, notes, synonyms, ICD-9-CM conversion, index and annotation crosswalks, DRG grouping and more.
Hiroshima, Japan - Researchers have identified a second path to defeating chronic myelogenous leukemia, which tends to affect older adults, even in the face of resistance to existing drugs. The new findings were published on September 17th in Nature Communications.. Almost all patients with chronic myelogenous leukemia, or CML, have a faulty, cancer-causing gene, or oncogene called BCR-ABL1. BCR-ABL1 turns a regular stem cell (a unique type of cell that can turn into other types of cells and then reproduce those cells during life time) in the bone marrow into a CML stem cell that produces malformed blood cells. And instead of the CML stem cell dying when it should be scheduled to do so, the oncogene causes it to keep producing even more of these faulty blood cells.. Advances in treatment since the turn of the millennium have been extremely successful at combatting the disease in patients with this oncogene. Drugs called tyrosine kinase inhibitors (TKI) have completely transformed the prognosis ...
Chronic myelogenous leukemia (CML) is slow-progressing and associated with a specific genetic abnormality in the cell, called the Philadelphia chromosome.
Gómez-Castañeda, E., Hopcroft, L.E.M. , Rogers, S. , Jorgensen, H.G., Pellicano, F., Vetrie, D. , Copland, M. , Grimmond, S. and Holyoake, T.L. (2016) Uncovering the BCR-ABL1 Tyrosine Kinase Independent Signature in Chronic Myeloid Leukaemia Stem Cells. 36th World Congress of the International Society of Hematology, Glasgow, Scotland, 18-21 Apr 2016. (doi:10.1111/bjh.14019) Full text not currently available from Enlighten. ...
The purpose of this study is to find out if multiple tyrosine kinase inhibitor resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) can be treated with combination approach of Nilotinib with Ruxolitinib which may block alternative pathway besides BCR-ABL kinase inhibition in Ph positive leukemia, esp against JAK2-STAT5 pathway. First step is to define the dose of Ruxolitinib with fixed dose of Nilotinib which had been approved at the dose of 400mg bid for imatinib failed CML.. During phase I part of the study,dose escalations will be decided on the basis of DLTs observed hence the exact sample size could not be predicted with certainty but will range between 9-12 patients. Three patients will be enrolled per dose level. Accordingly 9 patients are expected to be enrolled. If a DLT is observed, 3 more patients will be enrolled at the dose level in which the DLT occurred.. The study will be conducted at multiple sites across Canada and enrollment will be competitive. Once ...
Cepheids Xpert BCR-ABL Ultra is a quantitative test for BCR-ABL major breakpoint (p210) transcripts that provides highly sensitive and on-demand molecular results.
Ponatinib is a tyrosine kinase inhibitor (TKI) that blocks the action of the BCR-ABL protein. It is only used in patients with CML if the other TKIs havent worked or if there is a T315I mutation (gene change) in the BCR-ABL protein. This mutation can occur in some CML patients and the mutation can prevent other TKIs from working. This drug can be used to treat: Chronic,
Chronic myelogenous leukemia (CML) is the type of cancer of the blood cells, deadly because it progresses more slowly than the acute forms of leukemia. A lot of white cells, known as granulocytes, are produced by the bone marrow, gradually crowding the bone marrow, and interfering with the normal production of blood cells. This is the forum for discussing anything related to this health condition
Chronic myelogenous leukemia (cml) | Chemotherapy and immunotherapy. Cancer: Treatment in Aachen, Germany ✈. Prices on - booking treatment online!
An established second-line drug for chronic myelogenous leukemia has high response rates when given to newly diagnosed patients as their first therapy for the disease, according to early results from...
The Bcr-Abl protein-tyrosine kinase is implicated in the development of chronic myeloid leukemia. The potential role of protein-tyrosine phosphatase in the regulation of Bcr-Abl signaling was explored. First, expression patterns of tyrosine phosphatases in leukemic cell lines were investigated using …
Chronic myelogenous leukemia (CML) originates in a pluripotent hematopoetic stem cell of the bone marrow and is characterized by greatly increased numbers of granulocytes in the blood. Myeloid and oth
The 3 phases of chronic myelogenous leukemia (CML), as defined by the World Health Organization (WHO),{ref1}{ref2} are listed below. Table. Phases of Chronic MyelogenousCML phase WHO defini... more
Keep up to date with the latest Chronic myelogenous leukemia (CML) information from Patient Power. Join our newsletter to be the first to find out whats new.
City of Hope researchers may have discovered a more effective treatment for patients with chronic myelogenous leukemia (CML) according to a study published in Nature Medicine.
Chronic Myelogenous Leukemia is a cancer of the blood and bone marrow. Learn about the risk factors, symptoms, diagnosis and treatment at UVA.
Question - Menopausal due to chronic myelogenous leukemia. Diagnosed with fluid in cyst. Will it lead to cancer?. Ask a Doctor about when and why Ultra sound is advised, Ask an Oncologist
"Flow cytometric immunobead assay for the detection of BCR-ABL fusion proteins in leukemia patients". Leukemia. 23 (6): 1106-17 ... Also detection of fusion proteins using immunobead assays was introduced. Van Dongen, J J M; Orfao, A; Euroflow, Consortium ( ... epitopes of proteins involved in chromosomal translocations were developed for detection of most frequent fusion proteins in ... "Detection of fusion genes at the protein level in leukemia patients via the flow cytometric immunobead assay". Best Practice & ...
JAK2 phosphorylates the BCR-ABL fusion protein at Y177 and stabilizes the fusion protein, strengthening tumorigenic cell ... This gene encodes for a BCR-ABL fusion protein. Depending on the precise location of fusion, the molecular weight of this ... The ABL tyrosine kinase activity of BCR-Abl is elevated relative to wild-type ABL.[11] Since ABL activates a number of cell ... bcr-abl+Fusion+Proteins at the US National Library of Medicine Medical Subject Headings (MeSH) ...
Other in vitro research indicates ITCs may affect levels of the BCR-ABL fusion protein, the oncoprotein active in leukemia. ...
... the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is ... Some tumor cells, however, have a dependence on bcr-abl. Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in ... After the Philadelphia chromosome mutation and hyperactive bcr-abl protein were discovered, the investigators screened chemical ... a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, ...
The fusion protein AML1-ETO is commonly found in acute myeloid leukemia patients. p14ARF is a well known tumor suppressor that ... BCR-Abl is constitutively active due chromosome translocation; therefore it over-phosphorylates the tyrosine kinase. Imatinib ... One of the hallmarks of M2 subtype acute myeloid leukemia is the formation of a fusion protein, AML1-ETO or RUNX1-RUNX1T1, due ... The direct consequence of having the fusion protein, AML1-ETO, is the lack of p53 regulation in pre-leukemic cells. Therefore, ...
It has also been shown to bind (in a different conformation from the VEGF binding) to the BCR-ABL fusion protein, specifically ... A study published in 2015 showed that axitinib effectively inhibits a mutated gene (BCR-ABL1[T315I]) that is common in chronic ... March 2015). "Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation". Nature. 519 (7541): 102-5. ...
... bcr-abl fusion protein - benzene - benzene ring - beta-2 microglobulin - beta adrenergic receptor - beta sheet - beta-1 ... protein - protein biosynthesis - Protein Data Bank - protein design - protein expression - protein folding - protein isoform - ... protein P16 - protein P34cdc2 - protein precursor - protein structure prediction - protein subunit - protein synthesis - ... proto-oncogene protein C-kit - proto-oncogene proteins c-abl - proto-oncogene proteins c-bcl-2 - Proto-oncogene proteins c-fos ...
... which occurs in chronic myelogenous leukemia and results in production of the BCR-abl fusion protein, an oncogenic tyrosine ... Another common example is the class of Bcr-Abl inhibitors, which are used to treat chronic myelogenous leukemia (CML). ... miRNAs do not code for proteins, but can "target" protein-coding genes and reduce their expression. Cancers usually arise from ... "Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast ...
... has been known for a long time to be a chromosomal translocation creating an abnormal fusion protein, kinase BCR-ABL, which ... Although monoclonal antibodies (immune proteins which can be selected to precisely bind to almost any target) have been around ... "Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571". J. Biol. Chem. 277 (35): 32214-9. ...
... groel protein MeSH D12.776.602.500.500.100 - fusion proteins, bcr-abl MeSH D12.776.602.500.500.320 - fusion proteins, gag-onc ... oncogene protein tpr-met MeSH D12.776.624.664.500.100 - fusion proteins, bcr-abl MeSH D12.776.624.664.500.320 - fusion proteins ... fusion proteins, gag-pol MeSH D12.776.964.775.350.400 - hiv core protein p24 MeSH D12.776.964.775.375.325 - fusion proteins, ... oncogene protein v-maf MeSH D12.776.964.700.750.875 - oncogene proteins v-abl MeSH D12.776.964.700.750.882 - oncogene proteins ...
The first, dasatinib, blocks several further oncogenic proteins, in addition to more potent inhibition of the BCR-ABL protein, ... encouraging but mixed results of vaccination were reported with the BCR/ABL1 p210 fusion protein in patients with stable ... but since the 2000s have been replaced by Bcr-Abl tyrosine-kinase inhibitors drugs that specifically target BCR-ABL, the ... In 2012, Radotinib joined the class of novel agents in the inhibition of the BCR-ABL protein and was approved in South Korea ...
In in vitro studies of chronic myelogenous leukemia (CML), siRNA was used to cleave the fusion protein, BCR-ABL, which prevents ... Cleaving the fusion protein reduced the amount of transformed hematopoietic cells that spread throughout the body by increasing ... Gene silencing can be used to treat HD by targeting the mutant huntingtin protein. The mutant huntingtin protein has been ... Through this approach, instead of targeting SNPs on the mutated protein, all of the normal and mutated huntingtin proteins are ...
Recent studies have also shown that Bcr-Abl, the fusion protein responsible for chronic myelogenous leukemia (CML), ... "Depletion of Pleckstrin Homology Domain Leucine-rich Repeat Protein Phosphatases 1 and 2 by Bcr-Abl Promotes Chronic ... Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that ... The PHLPP isoforms (PH domain and Leucine rich repeat Protein Phosphatases) are a pair of protein phosphatases, PHLPP1 and ...
Another important role of Hsp90 in cancer is the stabilization of mutant proteins such as v-Src, the fusion oncogene Bcr/Abl, ... Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against ... However, when cells are heated, the fraction of heat shock proteins increases to 4-6% of cellular proteins. Heat shock protein ... A 90 kDa protein is considered fairly large for a non-fibrous protein. Hsp90 is found in bacteria and all branches of eukarya, ...
... and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase. Small-scale mutations include point ... Within this protein-coding DNA (called the exome), an average cancer of the breast or colon can have about 60 to 70 protein ... Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and ... They often produce mitogens, or are involved in transcription of DNA in protein synthesis, which create the proteins and ...
... in which the BCR-ABL fusion gene (the product of a reciprocal translocation between chromosome 9 and chromosome 22) is present ... These medications specifically inhibit the Ableson tyrosine kinase (ABL) protein and are thus a prime example of "rational drug ... In specific, proteomics is used to analyze a series of protein expressions, instead of a single biomarker. Proteins control the ... of cases and produces hyperactivated abl-driven protein signaling. ...
"Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein" ( ... presumably due to the downregulation of surface adhesion molecules by bcr:abl. However, another study suggests that bcr:abl ... The cells are non-adherent and rounded, are positive for the bcr:abl fusion gene, and bear some proteomic resemblance to both ... There are many different cellular components involved in the cycle of apoptosis such as BCR/ABL, Bcl-2, Bax protein, and ...
... a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein that is characteristic for Philadelphia ... "Consensus scoring for enriching near-native structures from protein-protein docking decoys". Proteins. 75 (2): 397-403. doi: ... an antiviral drug 5-HT3 antagonists Acetylcholine receptor agonists Angiotensin receptor antagonists Bcr-Abl tyrosine-kinase ... The purified protein is then used to establish a screening assay. In addition, the three-dimensional structure of the target ...
Choo et al designed a protein consisting of three zinc-finger domains that targeted a specific sequence on a BCR-ABL fusion ... Designer zinc-finger proteins are engineered proteins used to target specific areas of DNA. These proteins capitalize on the ... If a methylase domain is bound to the designer zinc-finger protein, when the zinc-finger protein binds to the target DNA ... thereby ensuring that the protein motif is highly selective of its target. In engineering a designer zinc-finger protein, ...
Daley demonstrated that a fusion protein called bcr-abl is sufficient to stimulate cell growth and cause chronic myelogenous ... which deactivates bcr-abl proteins. Gleevec has shown impressive results in treating chronic myelogenous leukemia and also ... In 1980, his group isolated the oncogene in AMuLV and showed it was a member of a new class of protein kinases that used the ... Brandt VL, Roth DB (January 2008). "G.O.D.'s Holy Grail: discovery of the RAG proteins". Journal of Immunology. 180 (1): 3-4. ...
Common examples of predictive biomarkers are genes such as ER, PR and HER2/neu in breast cancer, BCR-ABL fusion protein in ... February 2011). "Mutant proteins as cancer-specific biomarkers". Proceedings of the National Academy of Sciences of the United ... More specifically, a biomarker indicates a change in expression or state of a protein that correlates with the risk or ... The most extreme case would be to detect mutant proteins as cancer specific biomarkers through Selected reaction monitoring ( ...
Treatment of chronic myeloid leukemia (CML) involves a tyrosine kinase inhibitor that targets the BCR/ABL fusion gene called ... These point mutations enhance autophosphorylation of the BCR-ABL protein, resulting in the stabilization of the ATP-binding ... In some people resistant to Imatinib, the BCR/ABL gene is reactivated or amplified, or a single point mutation has occurred on ... This transporter protein is encoded by the MDR1 gene and is also called the ATP-binding cassette (ABC) protein. MDR1 has ...
Common examples of predictive biomarkers are genes such as ER, PR and HER2/neu in breast cancer, BCR-ABL fusion protein in ... The most extreme case would be to detect mutant proteins as cancer specific biomarkers through Selected reaction monitoring ( ... SRM), since mutant proteins can only come from an existing tumor, thus providing ultimately the best specificity for medical ... the protein Oct-4 is used as a biomarker to identify embryonic stem cells).[19] ...
Often, fusion genes are oncogenes that cause cancer; these include BCR-ABL, TEL-AML1 (ALL with t(12 ; 21)), AML1-ETO (M2 AML ... The protein synthesized when a fusion gene is expressed is called a fusion protein. ETV6-NTRK3 gene fusion List of RNA-Seq ... For example, by creating a fusion gene of a protein of interest and green fluorescent protein, the protein of interest may be ... ChiPPI: The Server Protein-Protein Interaction of Chimeric Proteins. ChimerDB 2.0: a knowledgebase for fusion genes updated. ...
Examples include: Gag-onc fusion protein Bcr-abl fusion protein Tpr-met fusion protein Antibodies are fusion proteins produced ... The bcr-abl fusion protein is a well-known example of an oncogenic fusion protein, and is considered to be the primary ... Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created ... A recombinant fusion protein is a protein created through genetic engineering of a fusion gene. This typically involves ...
Although the BCR-ABL fusion protein has been extensively studied, the function of the normal BCR gene product is not clear. The ... oligomerisation domain found at the N-terminus of BCR is essential for the oncogenicity of the BCR-ABL fusion protein. The BCR- ... The translocation produces a fusion protein that is encoded by sequence from both BCR and ABL, the gene at the chromosome 9 ... BCR+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH) Human BCR genome location and BCR ...
Rous sarcoma virus Fusion protein Fusion gene Fusion transcript Chimeric gene Bcr-abl fusion protein Oncovirus Retrovirus ... a Gag-v-Onc fusion protein from the Rous sarcoma virus is useful in illustrating the dual role that the fusion protein plays in ... The gag-onc fusion protein (also written as Gag-v-Onc, with "v" indicating that the Onc sequence resides in a viral genome) is ... When this type of gene is translated to a protein, the protein is called a "transforming protein". Note that since the viral ...
Bcr-Abl was regarded as highly attractive target for drug intervention since the Bcr-Abl fusion gene encodes a constitutively ... Point mutations can cause amino acid substitutions inside the kinase domain of the Bcr-Abl protein and disrupt the binding site ... Bcr-Abl dependent mechanisms include over expression or amplification of the Bcr-Abl gene and point mutations within the Bcr- ... Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase that ...
fusion protein against VEGF (Aflibercept). *proapoptotic peptide against ANXA2 and prohibitin (Adipotide) ... "Breast cancer research : BCR. 3 (2): 86-90. doi:10.1186/bcr276. PMC 138676. PMID 11250751.. ... The CD20 proteins are sticking out of the cell membrane, and rituximab, the Y-shaped antibody, is binding to the CD20 proteins. ... The antibody binds to the cell surface protein CD20. CD20 is widely expressed on B cells, from early pre-B cells to later in ...
fusion protein against VEGF (Aflibercept). *proapoptotic peptide against ANXA2 and prohibitin (Adipotide) ... bcr-abl *Bosutinib. *Dasatinib. *Imatinib. *Nilotinib. *Ponatinib. *Radotinib. *Src (Bosutinib. *Dasatinib). *Janus kinase * ... Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7). *Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1) ... Like lapatinib and neratinib, afatinib is a protein kinase inhibitor that also irreversibly inhibits human epidermal growth ...
Philadelphia chromosome t(9 ABL; 22 BCR). *Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) ... The resulting BLM protein is defective. the defect in RecQ an helicase facilitates the defective unwinding of DNA during ... However, the two genotypes arise from the fusion of more than one fertilized zygote in the early stages of embryonic ... commonly the green fluorescent protein or GFP) and an allele of a gene to be studied (both on chromosomes bearing FRT sites). ...
It is 10-30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl ... fusion protein against VEGF (Aflibercept). *proapoptotic peptide against ANXA2 and prohibitin (Adipotide) ... Nilotinib inhibits the kinases BCR-ABL,[16] KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK.[17] ... See also: Discovery and development of Bcr-Abl tyrosine kinase inhibitors. Nilotinib was developed by Novartis.[3] It was ...
BCR-ABL fusion(P185)[34]. 1.6%[32]. t(4;11)(q21;q23) MLL-AF4 fusion[35]. 1.6%[32]. ... The result is the combination of two usually separate proteins into a new fusion protein. This protein can have a new function ... RUNX1 fusion gene that combines two factors that promote blood cell development and the BCR-ABL1 fusion gene of the ... Person with t(9,22) positive-ALL (30% of adult ALL cases) and other Bcr-abl-rearranged leukemias are more likely to have a poor ...
This fusion protein has enzyme activity that can be inhibited by imatinib, a small molecule drug.[119][120][121][122] ... bcr-abl *Imatinib. *Dasatinib. *Nilotinib. *Ponatinib. *Radotinib. *Src (Bosutinib. *Dasatinib). *Janus kinase *Lestaurtinib ... As different proteins are utilised by different cancer types, the targeted therapy drugs are used on a cancer type specific, or ... Now it is clear that there is often a range of protein targets that the drug can bind. An example target for targeted therapy ...
... which occurs in chronic myelogenous leukemia and results in production of the BCR-abl fusion protein, an oncogenic tyrosine ... Another common example is the class of Bcr-Abl inhibitors, which are used to treat chronic myelogenous leukemia (CML).[4] ... "Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast ... miRNAs do not code for proteins, but can "target" protein-coding genes and reduce their expression. ...
fusion protein against VEGF (Aflibercept). *proapoptotic peptide against ANXA2 and prohibitin (Adipotide) ... bcr-abl *Imatinib. *Dasatinib. *Nilotinib. *Ponatinib. *Radotinib. *Src (Bosutinib. *Dasatinib). *Janus kinase *Lestaurtinib ... Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7). *Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1) ... recruiting the phosphotyrosine-binding proteins to EGFR to assemble protein complexes that transduce signal cascades to the ...
... a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein that is characteristic for Philadelphia ... "Consensus scoring for enriching near-native structures from protein-protein docking decoys". Proteins. 75 (2): 397-403. doi: ... Represent and cluster candidates according to protein-ligand 3D information. *Needs meaningful representation of protein-ligand ... "Protein-peptide docking: opportunities and challenges". Drug Discovery Today. 2018-05-04. doi:10.1016/j.drudis.2018.05.006. ...
Resistance to BCR-ABL targeting drugs[edit]. In the case of Gleevec (Imatinib), which targets the BCR-ABL fusion gene in ... Alterations in co-regulatory proteins *Interactions between the SERM, ER, and co-regulatory proteins may influence whether the ... "Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency". ... Epigeneticically deficient DNA repair proteins include BRCA1, WRN, MGMT, MLH1, MSH2, ERCC1, PMS2, XPF, P53, PCNA and OGG1, and ...
... abl fusion protein na isang oncogenic tyrosine kinase. Ang maliit na iskalang mga mutasyon ay kinabibilangan ng mga puntong ... ng mga kromosomang 9 at kromosomang 22 na nangyayari sa kronikong myelogenous leukemia at nagreresulta sa produksiyon ng BCR- ... Ang mga pagsubok na ito ay maaaring magbigay ng impormasyon tungkol sa mga pagbabagong molekular(gaya ng mga mutasyon, fusion ...
... with either the formation of hybrid genes and fusion proteins, deregulation of genes and overexpression of proteins, or loss of ... Philadelphia chromosome t(9 ABL; 22 BCR). *Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) ... making it difficult for cells to properly control how much protein is made. Producing too much or too little protein can have ... "Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer". Archived from the original on 2016-05-29.. ...
... potentially bringing together separate genes to form functionally distinct fusion genes (e.g., bcr-abl). ... producing a fusion protein (FIG-ROS). The abnormal FIG-ROS fusion protein has constitutively active kinase activity that causes ... "Lifeless' prion proteins are 'capable of evolution'". Health. BBC News Online. London. 1 January 2010. Archived from the ... By impact on protein sequenceEdit. *A frameshift mutation is a mutation caused by insertion or deletion of a number of ...
fusion protein against VEGF (Aflibercept). *proapoptotic peptide against ANXA2 and prohibitin (Adipotide) ... bcr-abl *Bosutinib. *Dasatinib. *Imatinib. *Nilotinib. *Ponatinib. *Radotinib. *Src (Bosutinib. *Dasatinib). *Janus kinase * ... "Analplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer". UpToDate. Wolters Kluwer. Retrieved 30 ... "Anapestic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer". UpToDate. Wolters Kluwer. Retrieved 30 ...
fusion protein against VEGF (Aflibercept). *proapoptotic peptide against ANXA2 and prohibitin (Adipotide) ... bcr-abl *Imatinib. *Dasatinib. *Nilotinib. *Ponatinib. *Radotinib. *Src (Bosutinib. *Dasatinib). *Janus kinase *Lestaurtinib ... Excreting protein [usually plasma proteins] in the urine. Not dangerous in itself but it is indicative kidney damage ... Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7). *Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1) ...
Bcr-Abl tyrosine-kinase inhibitor. *Protein kinase inhibitor. References[edit]. *^ Yaish P, Gazit A, Gilon C, Levitzki A (1988 ... fusion protein against VEGF (Aflibercept). *proapoptotic peptide against ANXA2 and prohibitin (Adipotide) ... Crystal structure of the second generation Bcr-Abl tyrosine-kinase inhibitor nilotinib (red) in complex with an Abl kinase ... "Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells". Nat Med. 2 (5): 561-6. ...
"BCR-ABL". This fused gene encodes for a protein that displays high protein tyrosine kinase activity (this activity is due to ... translocation events that lead to a fusion between a proto-oncogene and a 2nd gene (this creates a fusion protein with ... An increase in the amount of a certain protein (protein concentration), caused by *an increase of protein expression (through ... Another example of an oncogene is the Bcr-Abl gene found on the Philadelphia chromosome, a piece of genetic material seen in ...
fusion protein against VEGF (Aflibercept). *proapoptotic peptide against ANXA2 and prohibitin (Adipotide) ... bcr-abl *Imatinib. *Dasatinib. *Nilotinib. *Ponatinib. *Radotinib. *Src (Bosutinib. *Dasatinib). *Janus kinase *Lestaurtinib ... Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7). *Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1) ... In the blood, it is almost completely (90-96%) bound to plasma proteins such as albumin. It is metabolised to N- ...
Bcr-Abl tyrosine-kinase inhibitors. *Cannabinoid receptor antagonists. *CCR5 receptor antagonists. *Neurokinin 1 receptor ... Receptor protein serine/threonine kinase (EC *Bone morphogenetic protein receptors *BMPR1 ... In general, protein kinases are classified in two major categories based on their substrate specificity, protein tyrosine ... PIKKs have four domains at the protein level, which distinguish them from other protein kinases. From the N-terminus to the C- ...
Philadelphia chromosome t(9 ABL; 22 BCR). *Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) ... Out of the 4 types of ALCL, one subtype of systemic ALCL expresses the protein anaplastic lymphoma kinase (ALK); the other ... The product of this fusion gene may be identified by immunohistochemistry for ALK. The nucleophosmin component associated with ... These lymphomas show immunopositivity for ALK protein in 70% of cases. They are also typically positive for EMA. In contrast to ...
Bcr-Abl tyrosine-kinase inhibitors. *Cannabinoid receptor antagonists. *CCR5 receptor antagonists. *Neurokinin 1 receptor ... is required to cleave a viral polyprotein precursor into individual mature proteins. The viral RNA and viral proteins assemble ... This fusion creates a pore through which the viral capsid enters the cell.[13] Following entry into the cell the RNA of the ... When HIV infects its target cell it requires fusion of the viral and cellular membranes.[12] The first step is the interaction ...
The BCR-ABL protein can be inhibited by various small molecules. One such inhibitor is imatinib mesylate, which occupies the ... This new fusion gene, BCR-ABL, encodes an unregulated, cytoplasm-targeted tyrosine kinase that allows the cells to proliferate ... Second generation BCR-ABL tyrosine-kinase inhibitors are also under development to inhibit BCR-ABL mutants resistant to ... "Bcr and Abl interaction: oncogenic activation of c-Abl by sequestering Bcr". Cancer Res. 63 (2): 298-303. PMID 12543778. ...
"Identification of a protein that binds to the SH3 region of Abl and is similar to Bcr and GAP-rho". Science. 257 (5071): 803-6 ... v-Crk, a transforming oncoprotein from avian sarcoma viruses, is a fusion of viral "gag" protein with the SH2 and SH3 domains ... Feller SM, Knudsen B, Hanafusa H (1994). "c-Abl kinase regulates the protein binding activity of c-Crk". EMBO J. 13 (10): 2341- ... Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the CRK gene. The CRK protein ...
"Identification of a protein that binds to the SH3 region of Abl and is similar to Bcr and GAP-rho". Science. 257 (5071): 803-6 ... 2000). "The interaction between EEN and Abi-1, two MLL fusion partners, and synaptojanin and dynamin: implications for ... Zhang B, Zheng Y (1998). "Regulation of RhoA GTP hydrolysis by the GTPase-activating proteins p190, p50RhoGAP, Bcr, and 3BP-1 ... SH3 domain-binding protein 1 is a protein that in humans is encoded by the SH3BP1 gene. GRCh38: Ensembl release 89: ...
tr,B0ZRR0,B0ZRR0_HUMAN BCR/ABL e8a2 fusion protein (Fragment) OS=Homo sapiens OX=9606 GN=BCR/ABL fusion PE=2 SV=1 ... BCR/ABL e8a2 fusion proteinImported. ,p>Information which has been imported from another database using automatic procedures.,/ ... Name:BCR/ABL fusionImported. Automatic assertion inferred from database entriesi ... to allow unambiguous identification of a protein.,p>,a href=/help/protein_names target=_top>More...,/a>,/p>Protein namesi. ...
tr,A9UF07,A9UF07_HUMAN BCR/ABL fusion protein isoform Y5 OS=Homo sapiens GN=BCR/ABL fusion PE=2 SV=1 ... Pfam protein domain database. More...Pfami. View protein in Pfam. PF09036. Bcr-Abl_Oligo. 1 hit. PF08919. F_actin_bind. 1 hit. ... Pfam protein domain database. More...Pfami. View protein in Pfam. PF09036. Bcr-Abl_Oligo. 1 hit. PF08919. F_actin_bind. 1 hit. ... BCR/ABL fusion protein isoform Y5Imported. ,p>Information which has been imported from another database using automatic ...
"Fusion Proteins, bcr-abl" by people in this website by year, and whether "Fusion Proteins, bcr-abl" was a major or minor topic ... Proto-Oncogene Proteins c-abl [D08.811.913.696.620.682.725.500]. *Fusion Proteins, bcr-abl [D08.811.913.696.620.682.725.500.500 ... Fusion Proteins, bcr-abl*Fusion Proteins, bcr-abl. *Fusion Proteins, bcr abl ... "Fusion Proteins, bcr-abl" is a descriptor in the National Library of Medicines controlled vocabulary thesaurus, MeSH (Medical ...
... compared the function of the ABL/BCR proteins with that of wild-type BCR. We investigated the effects of BCR and ABL/BCRs i.) ... ABL/BCR fusion proteins in comparison to their physiological counterpart BCR. ... ABL/BCR) fusion transcript, detectable in about 65% patients suffering from chronic myeloid leukemia, or the p96(ABL/BCR) ... The ABL/BCRs are N-terminally truncated BCR mutants. The fact that BCR contains Rho-GEF and Rac-GAP functions strongly suggest ...
Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele- ... Fusion Proteins, bcr-abl / chemistry * Fusion Proteins, bcr-abl / genetics* * Hematopoietic Stem Cells / metabolism ... Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL ... all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in ...
Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease. ... Different mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. ... Fusion Proteins, bcr-abl * Humans * Imatinib Mesylate * Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy* ... STI571, a competitive inhibitor at the ATP-binding site of BCR-ABL, has been shown to have high activity in this type of ...
Creative Peptides offers BCR/ABL 210 kD fusion protein (259-269) for your research. We also provide custom peptide synthesis, ... Home > Therapeutic Peptides > Tumor Antigen Derived Peptides > BCR/ABL 210 kD fusion protein (259-269) ... BCR/ABL 210 kD fusion protein (259-269) (ta-571). * Project Description:. ...
Giles, F. J., Cortes, J. E., & Kantarjian, H. M. (2005). Targeting the kinase activity of the BCR-ABL fusion protein in ... Giles, Francis J. ; Cortes, Jorge E. ; Kantarjian, Hagop M. / Targeting the kinase activity of the BCR-ABL fusion protein in ... Targeting the kinase activity of the BCR-ABL fusion protein in patients with chronic myeloid-leukemia. / Giles, Francis J.; ... Giles, FJ, Cortes, JE & Kantarjian, HM 2005, Targeting the kinase activity of the BCR-ABL fusion protein in patients with ...
... we have used the human BV173 and the mouse BaF3/Bcr-Abl-expressing cell lines as model systems to investigate the molecular ... 0/DNA-Binding Proteins; 0/FOXO1 protein, human; 0/Forkhead Transcription Factors; 0/Fusion Proteins, bcr-abl; 0/Membrane ... Fusion Proteins, bcr-abl / metabolism*. Humans. Membrane Proteins / genetics*. Mice. Molecular Sequence Data. Piperazines / ... FoxO3a lies downstream of Bcr-Abl signalling and is constitutively phosphorylated in the Bcr-Abl-positive BV173 and BaF3/Bcr- ...
... creating the dominant oncogene BCR/abl at the junction point. The specific function of the BCR/abl fusion protein is not ... Other articles where BCR/abl is discussed: human genetic disease: Genetics of cancer: …9, ... 9, creating the dominant oncogene BCR/abl at the junction point. The specific function of the BCR/abl fusion protein is not ...
The e1a3 rare variant is produced by the fusion of BCR exon 1 to ABL exon 3. The presence of this translocation has been ... We report two new cases of B-ALL Ph+ with the rare e1a3 fusion transcript. The e1a3 and e1a2 (p190) transcripts have been ... several types of BCR-ABL fusion proteins may appear [5]. To date, three main breakpoint cluster regions in the BCR gene have ... b2a3 and e6a2 of BCR-ABL have been described. The e1a3 variant is produced by the fusion of BCR exon 1 to ABL exon 3. The ...
... a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the ... We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a ... We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive ... Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with ...
JAK2 phosphorylates the BCR-ABL fusion protein at Y177 and stabilizes the fusion protein, strengthening tumorigenic cell ... This gene encodes for a BCR-ABL fusion protein. Depending on the precise location of fusion, the molecular weight of this ... The ABL tyrosine kinase activity of BCR-Abl is elevated relative to wild-type ABL.[11] Since ABL activates a number of cell ... bcr-abl+Fusion+Proteins at the US National Library of Medicine Medical Subject Headings (MeSH) ...
BCR/ABL gene explanation free. What is BCR/ABL gene? Meaning of BCR/ABL gene medical term. What does BCR/ABL gene mean? ... Looking for online definition of BCR/ABL gene in the Medical Dictionary? ... M-BCR) on chromosome 22. The fusion gene produces a specific protein, P210. This fusion gene is found in chronic myelocytic ... BCR/ABL gene. BCR/ABL gene (jēn) A fusion gene produced when a segment of the Abelson protooncogene, ABL, from chromosome 9, ...
Polymerase chain reaction (PCR) positive fusion transcripts for BCR/ABL. *BCR/ABL translocation present by fluorescence in situ ... BCR/ABL protein detectable by immunoblotting. *BCR/ABL rearrangement detectable by Southern blot analysis ... Leukemia, Myelogenous, Chronic, BCR-ABL Positive. Neoplasms by Histologic Type. Neoplasms. Myeloproliferative Disorders. Bone ... A Phase III Study of Interferon-Refractory Patients With BCR/ABL(+) Chronic Myelogenous Leukemia (CML) Treated With ...
BCR-ABL fusion gene. The BCR-ABL fusion gene (also called the Philadelphia chromosome) is formed when pieces of chromosomes 9 ... This change causes abnormal proteins called TRK fusion proteins, which may cause cancer cells to grow. NTRK gene fusions are ... have the BCR-ABL fusion gene.. People with certain types of leukemia who test positive for the BCR-ABL fusion gene may benefit ... NTRK gene fusions. The neurotrophic tyrosine receptor kinase (NTRK) gene tells nerve cells to make a protein that helps the ...
Fusion Proteins, bcr-abl. *Childhood Cancer. *Knockout Mice. *Mutation. *Chromosome 7. *Siblings ... The resulting BCR-ABL1 fusion gene, encoding a tyrosine kinase with deregulated activity, has a central role in the ... in BCR-ABL1-negative but not in BCR-ABL1-positive B cell ALL patients. Our meta-analysis suggests that IKZF1 deletion is a poor ... Protein signaling and regulation of gene transcription in leukemia: role of the Casein Kinase II-Ikaros axis.. J Investig Med. ...
Fusion Proteins, bcr-abl. *Chromosome 19. *Adolescents. *Young Adult. *Mutation. *Tumor Necrosis Factor Receptor Superfamily, ... protein binding - protein complex - protein dimerization activity - protein heterodimerization activity - protein ... helix-loop-helix proteins. E proteins play a critical role in lymphopoiesis, and the encoded protein is required for B and T ... Common fusion transcripts ETV6-RUNX1, E2A-PBX, BCR-ABL1 and MLL-AF4 were examined by RT-PCR and noted in 15%, 15%, 13% and 1.4 ...
... the first dedicated database of human translocating proteins (URL: The core of the ... bcr-abl) fusion protein is found in patients with LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE. The p190(bcr-abl) fusion ... Fusion Proteins, Bcr-abl. Translation products of a fusion gene derived from CHROMOSOMAL TRANSLOCATION of C-ABL GENES to the ... Sumo-1 Protein. A 1.5-kDa small ubiquitin-related modifier protein that can covalently bind via an isopeptide link to a number ...
Fusion Proteins, bcr-abl/antagonists & inhibitors*. *Fusion Proteins, bcr-abl/chemistry*. *Fusion Proteins, bcr-abl/metabolism ... B) Bcr-Abl WT, Bcr-Abl I164E, Bcr-Abl T231R, and Bcr-Abl I164E/T231R constructs were coexpressed with HA-tagged paxillin in ... In vitro kinase activity of immunoprecipitated Bcr-Abl and the indicated constitutive active Abl mutant proteins (B, Bcr-Abl, C ... Bcr-Abl I164E Sensitized WT and Imatinib-Resistant Bcr-Abl Forms to TKI Inhibition. (A, B, D, and E) Kinase activity of the ...
Ab72493 is a protein fragment produced in Baculovirus infected Sf9 cells and has been validated in WB, SDS-PAGE. Abcam… ... BCR/ABL FUSION GENE, INCLUDED. *BCR/FGFR1 chimera protein. *BCR/FGFR1 FUSION GENE, INCLUDED ... This region is essential for the activation of the ABL1 tyrosine kinase and transforming potential of the chimeric BCR-ABL ... The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). ...
Prior treatment with a Oncogene fusion protein (BCR-ABL) inhibitor. *Extramedullary involvement of the testicles ... The number of Ph+ ALL participants with BCR-ABL Mutations at Disease Progression or Relapse was reported for each arm. ... Number of Participants With BCR-ABL Mutations at Time of Disease Progression [ Time Frame: Approximately 3 years ]. ...
Resistance typically occurs through increased expression of the bcr-abl protein or mutations in the fusion gene itself. ... bcr-abl, Src, c-Kit and PDGFR and is more than 300 times more potent than imatinib against cells expressing wild type bcr-abl( ... The bcr-abl gene is constitutively active (meaning it does not require activation by other proteins), and sends signals to ... After the Philadelphia chromosome mutation and defective bcr-abl protein were discovered, researchers screened chemical ...
myeloid-specific oncofusion proteins not directly linked to epigenetic alterations (e.g. BCR/ABL) ... and of myeloid leukemia-specific fusion genes (including MLL fusions, PML/RARA, AML1/ETO, DEK/CAN) as epigenetic modifiers ...
... expression of activating fusion proteins following translocations (e.g.,BCR-ABL and MALT1); or aberrant activation by ... The BCR-ABL fusion oncogene has been implicated in NF-κB activation, cell survival, and tumorigenesis in human leukemias (ref. ... 1A). Activation by a translocation that produces a MALT-1 fusion protein has reported in diffuse large B-cell lymphomas (ref. ... A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation. Genes Dev 1998;12:968-81. ...
... fusion gene encoded by the Philadelphia (Ph) chromosome. The BCR-ABL fusion protein(the formation... ... Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm companies with the BCR-ABL ... A 22-nucleotide fragment of a transfer RNA regulates translation by binding to the mRNA of a ribosomal protein and increasing ... The paralogous Brr6 and Brl1 are conserved integral membrane proteins of the nuclear envelope (NE) with an unclear role in ...
Fusion Proteins, bcr-abl/metabolism. Humans. Multidrug Resistance-Associated Proteins/genetics. Protein Kinase Inhibitors/ ... Protein Kinase Inhibitors); 0 (Pyrimidines); 0 (RNA, Messenger); EC (Fusion Proteins, bcr-abl); RBZ1571X5H (Dasatinib) ... Multidrug Resistance-Associated Proteins/physiology. Protein Kinase Inhibitors/pharmacology. Pyrimidines/pharmacology. [Mh] ... HHcy potentiated the reduction of free sulfide, H S and cystathionine γ-lyase protein, which converts L-cysteine to H S, in SMA ...
PTPROt inactivates the oncogenic fusion protein BCR/ABL and suppresses transformation of K562 cells. ... Role of de novo DNA methyltransferases and methyl CpG-binding proteins in gene silencing in a rat hepatoma. ...
PTPROt inactivates the oncogenic fusion protein BCR/ABL and suppresses transformation of K562 cells.. Lucas DM, Motiwala T, ...
Such defects may be related to underlying cytoskeletal changes induced by the p210BCR/ABL fusion protein. However, we report ... but comparing bone marrow-derived BCR/ABL dendritic cells (BCR/ABL BM-DC) with STI571-pretreated bone marrow-derived BCR/ABL ... BCR-ABL-Expressing Ba/F3 Cells. BCR/ABL gene transfer into Ba/F3 cells was done using MSCV p210 retrovirus as previously ... BCR/ABL is both a critical oncogene and a tumor-specific antigen in CML. The consequences of the BCR/ABL translocation on ...
  • Translation products of a fusion gene derived from CHROMOSOMAL TRANSLOCATION of C-ABL GENES to the genetic locus of the breakpoint cluster region gene on chromosome 22. (
  • The reciprocal (9;22) translocation fuses the bcr (breakpoint cluster region) gene on chromosome 22 to the abl (Abelson-leukemia-virus) gene on chromosome 9. (
  • Depending on the breakpoint on chromosome 22 (the Philadelphia chromosome - Ph+) the derivative 9+ encodes either the p40 (ABL/BCR) fusion transcript, detectable in about 65% patients suffering from chronic myeloid leukemia, or the p96 (ABL/BCR) fusion transcript, detectable in 100% of Ph+ acute lymphatic leukemia patients. (
  • On chromosome 22, translocation (9;22) involves the bcr (breakpoint cluster region) locus and there are two principal regions in which the breaks occur: (major) M-bcr, which spans between exons 12 to 16, and (minor) m-bcr, in the first intron, about 50 kb 5' of M-bcr. (
  • The abl/bcr fusion genes on 9+ differ depending on the breakpoint on chromosome 22. (
  • This chromosome is defective and unusually short because of reciprocal translocation , t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22 , and contains a fusion gene called BCR-ABL1 . (
  • This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle. (
  • The result is that a fusion gene is created by juxtaposing the ABL1 gene on chromosome 9 (region q34) to a part of the BCR (breakpoint cluster region) gene on chromosome 22 (region q11). (
  • A fusion gene produced when a segment of the Abelson protooncogene, ABL, from chromosome 9, translocates to the major breakpoint cluster region (M-BCR) on chromosome 22. (
  • As the field of genetics grew, it was discovered that the gene abl (pronounced "able"), normally located on chromosome 9, had attached itself to the gene bcr (pronounced "b-c-r") on chromosome 22. (
  • Chronic myelogenous leukemia (CML) is a human disease associated with a consistent chromosomal translocation that results in sequences from the c-abl locus on chromosome 9 being fused to sequences in a breakpoint cluster region (bcr) on chromosome 22. (
  • This fusion gene is the product of translocated chromosomes involving genes BCR (chromosome 22) and ABL (chromosome 9). (
  • These translocations fuse a breakpoint cluster region (BCR) derived from chromosome 22 to a portion of the c- ABL protooncogene from chromosome 9, thereby leading to formation of alternative BCR-ABL fusion proteins p210 BCR-ABL and p185 BCR-ABL (hereafter p210 and p185), which are typically detected in CML and Ph + ALL cells, respectively ( 3 - 5 ). (
  • Several investigators in the early 1980s showed that the Philadelphia chromosome translocation led to the formation of a new BCR/ABL1 fusion gene, composed of the 3' part of the ABL1 gene in the breakpoint on chromosome 9 and the 5' part of a gene called BCR in the breakpoint in chromosome 22. (
  • In 1985 it was clearly established that the fusion gene on chromosome 22 produced an abnormal chimeric BCR/ABL1 protein with the capacity to induce chronic myeloid leukemia. (
  • When this piece moves over to chromosome 22, part of the ABL gene attaches to the BCR gene. (
  • The changed chromosome 22, which contains the BCR-ABL gene, is called the Philadelphia chromosome because that's the city where researchers first discovered it. (
  • The importance of this kinase becomes apparent from the consequences of a specific, reciprocal translocation between chromosome 9 and chromosome 22 that yields a chimeric fusion protein, Bcr-Abl, in which the function of auto-regulatory mechanisms are inactivated. (
  • We have followed one patient with Philadelphia (Ph)-negative chronic myelogenous leukemia and identified an additional four patients from the literature who showed the rearrangement in the breakpoint cluster region ( bcr ) on chromosome 22 characteristic of Ph-positive chronic myelogenous leukemia. (
  • An example is the Philadelphia chromosome, a shortened chromosome 22, and the associated fusion protein BCR-ABL. (
  • The causative agent for 95% of all CML cases, Bcr-Abl, is derived from the fusion of the breakpoint cluster region (Bcr) gene on chromosome 22 and the Abelson leukemia oncogene (Abl) on chromosome 9. (
  • Giles, FJ , Cortes, JE & Kantarjian, HM 2005, ' Targeting the kinase activity of the BCR-ABL fusion protein in patients with chronic myeloid-leukemia ', Current Molecular Medicine , vol. 5, no. 7, pp. 615-623. (
  • BCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients. (
  • We investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. (
  • Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. (
  • After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. (
  • Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. (
  • This fusion gene is found in chronic myelocytic leukemia (CML). (
  • Note=A chromosomal aberration involving BCR is a cause of chronic myeloid leukemia. (
  • Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm companies with the BCR-ABL fusion gene encoded by the Philadelphia (Ph) chromosome. (
  • Chronic myelogenous leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl and treated with the tyrosine kinase inhibitor (TKI) imatinib. (
  • Barnes DJ, Palaiologou D, Panousopoulou E, Schultheis B, Yong AS, Wong A, Pattacini L, Goldman JM, Melo JV (2005) BCR-ABL expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. (
  • Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ (1994) Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. (
  • BCR/ABL fusion gene, encoding a paradigmatic tyrosine kinase involved in chronic myelogenous leukemia (CML), can modulate the expression of genes involved in natural killer (NK) cell target recognition. (
  • Chronic myelogenous leukemia (CML) is a clonal malignancy of the hematopoietic stem cell harboring a 9;22 translocation which fuses the ABL proto-oncogene to the ABL gene leading to constitutive tyrosine kinase activity necessary and sufficient for massive overproduction of granulocytic cells ( 1 ). (
  • BCR-ABL plays an essential role in the pathogenesis of chronic myeloid leukemia (CML) and some cases of acute lymphocytic leukemia (ALL). (
  • The BCR-ABL oncoprotein plays a central role in the pathogenesis of virtually all chronic myeloid leukemia (CML) and 15% to 30% of acute lymphocytic leukemia (ALL) cases ( 1 - 3 ). (
  • In contrast to MAPK inhibitors, dasatinib, a clinical drug directed against BCR-ABL, which is the cause of chronic myelogenous leukemia, affected nearly 1,000 phosphopeptides. (
  • Also new antibody clones against rigorously selected epitopes of proteins involved in chromosomal translocations were developed for detection of most frequent fusion proteins in acute leukemia and chronic myeloid leukemia. (
  • Acquired constitutive activation of protein tyrosine kinases is a central feature in the pathogenesis of chronic MPD. (
  • Network of tyrosine kinase fusion genes in eosinophilia-associated chronic myeloproliferative disorders. (
  • The BCR ABL fusion protein driving chronic myelogenous leukemia is the poster child for this approach. (
  • The prototypic example of this translocation is the BCR-ABL gene fusion in chronic myelogenous leukemia (CML). (
  • These include acute myeloid leukemia (AML) fueled by the gene FLT3, lung cancers fueled by genes EGFR and PDGFR, HER2-driven breast cancers, and BCR-ABL-fueled chronic myeloid leukemia (CML), according to Mohammad Azam, PhD , lead investigator and a member of the Division of Experimental Hematology and Cancer Biology. (
  • Cancer cells often become addicted to the mutated gene that causes them, such as BCR-ABL in kinase-driven chronic myeloid leukemia. (
  • en] This review article describes the identification of the tyrosine kinase BCR/ABL as the hallmark of chronic myeloid leukemias (CML) as well as the development of a specific inhibitor of this tyrosine kinase, the STI571 (Glivec, imatinib mesylate). (
  • Expression of Bcr-Abl, the oncogenic counterpart of the tyrosine kinase c-Abl, is the basis for chronic myelogenous leukemia (CML) ( 1 ). (
  • Although the ABL kinase inhibitor imatinib mesylate (Gleevec) provides highly effective treatment for BCR-ABL-positive chronic myelogenous leukemia, it has proven far less efficacious in the treatment of BCR-ABL-positive acute lymphoblastic leukemias (ALLs), many of which sustain deletions of the INK4A-ARF ( CDKN2A ) tumor suppressor locus. (
  • Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in chronic myeloid leukemia demonstrate that many patients with advanced stage disease respond initially but then relapse. (
  • Recent clinical trials of the Abelson tyrosine kinase (Abl) inhibitor STI-571 in chronic myeloid leukemia (CML) allow this question to be addressed directly in human cancer ( 4 , 5 ). (
  • In chronic myeloid leukemia,¿ he added, ¿the oncogene is an enzyme, a tyrosine kinase, that goes by the name BCR-ABL. (
  • As reported in Science , Sawyers described the clinical analysis of patients who had relapsed from early stage chronic CML to the late-stage blast crisis: ¿We examined the status of BCR-ABL in nine blast-crisis patients who had developed resistance to Gleevec. (
  • Imatinib is a small molecule inhibitor of the ABL in Chronic Myeloid Leukemia, Acute Myeloid Leukemia and Acute Lymphoblast Leukemia tumors that has been proven very successful in the clinic. (
  • Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. (
  • Background: Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses BCR to ABL resulting in deregulated ABL-tyrosine kinase activity. (
  • 3] BCR-ABL tyrosine kinase inhibitors in the treatment ofPhiladelphia chromosome positive chronic myeloid leukemia: a review. (
  • BCR-ABL is found in almost all patients with a type of leukemia called chronic myeloid leukemia (CML). (
  • A BCR-ABL test is most often used to diagnose or rule out chronic myeloid leukemia (CML) or a specific form of acute lymphoblastic leukemia (ALL) called Ph-positive ALL. (
  • You may need a BCR-ABL test if you have symptoms of chronic myeloid leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). (
  • Chronic myeloid leukemia (CML) is caused by the constitutively active Bcr-Abl tyrosine kinase. (
  • Identification of Philadelphia chromosome or BCR/ABL gene rearrangement in chronic myeloid leukemia is important at diagnosis as well as after treatment. (
  • The kinase inhibitor imatinib was developed to target the BCR-ABL tyrosine kinase fusion protein in treatment of chronic myelogenous leukemia ( 16 ). (
  • Furthermore, we have shown, for the first time, that bcr rearrangement in Ph-negative chronic myelogenous leukemia can result in expression of the aberrant 210-kilodalton bcr-abl fusion protein, which has been strongly implicated in Ph-positive leukemogenesis. (
  • Chronic myeloid leukemia (CML) is a rare myeloproliferative blood cancer that is characterized by the presence of the BCR-ABL fusion protein. (
  • This fusion protein drives nearly all cases of chronic myelogenous leukemia as well as some other types of leukemia. (
  • In the case of chronic myelogenous leukemia (CML), cytoplasmic Bcr-Abl causes oncogenesis/proliferation. (
  • Cepheid's Xpert BCR-ABL Ultra test solves many of the present challenges in monitoring patients with Chronic Myeloid Leukaemia , including accuracy (remarkably precise International Scale calibration) and speed (in hours) of reporting molecular response. (
  • Rationale for the recommendations for harmonizing current methodology for detecting BCR-ABL transcripts in patients with chronic myeloid leukaemia. (
  • In 1973, Janet Rowley, unraveled the cytogenetic anatomy of the Philadelphia chromosome, which subsequently led to the identification of the BCR-ABL1 fusion gene and its principal pathogenetic role in the development of chronic myeloid leukemia. (
  • The biology and treatment of patients with chronic myeloid leukemia (CML), a rare heterogeneous clonal hematopoietic stem cell disorder characterized by a consistent cytogenetic abnormality (the Philadelphia chromosome) and the presence of the BCR-ABL1 fusion gene, must surely be ranked as one of the most successful cancer medicine stories of the past century. (
  • The BCR-ABL1 fusion gene encodes the oncoprotein BCR-ABL1 (also referred to as p210 or BCR-ABL) with a constitutive active tyrosine kinase activity that is the primary cause of the chronic phase of CML. (
  • The product of fusion between M-bcr and abl is a protein of 210 kDa, the p210 ((BCR-ABL)) , which is highly specific for CML. (
  • Consequently, the hybrid BCR-ABL fusion protein is referred to as p210 or p185. (
  • Three clinically important variants encoded by the fusion gene are the p190, p210, and p230 isoforms. (
  • The fusion gene produces a specific protein, P210. (
  • CML cells have two novel products: an 8.5-kilobase RNA transcript containing both abl and bcr and a 210-kilodalton phosphoprotein (P210) recognized by v-abl-specific antisera. (
  • To test whether the P210 is the product of the novel 8.5-kilobase bcr/abl fusion transcript, antibodies were prepared against c-abl and bcr determinants. (
  • By using these reagents and v-abl-specific antisera, it was demonstrated that the P210 in CML cells is indeed the protein product of the 8.5-kilobase transcript. (
  • By analogy to the gag/abl fusion protein of Abelson murine leukemia virus, the replacement of amino terminal c-abl sequences by bcr sequences in P210 may create a transforming protein involved in CML. (
  • Mouse bone marrow cells transduced with retroviral vectors encoding either of two oncogenic Bcr-Abl isoforms (p210 Bcr-Abl and p185 Bcr-Abl ) induce B cell lympholeukemias when transplanted into lethally irradiated mice. (
  • Mice receiving Arf −/− or Arf +/− p210 Bcr-Abl -positive pre-B cells do not achieve remission when maintained on high doses of oral imatinib therapy and rapidly succumb to lympholeukemia. (
  • Treatment of Arf −/− , p210 Bcr-Abl -positive pre-B cells with imatinib together with an inhibitor of JAK kinases abrogates this resistance, suggesting that this combination may prove beneficial in the treatment of BCR-ABL-positive acute lymphoblastic leukemia. (
  • 3 of 16 children expressed both m-BCR/ABL and M-BCR/ABL transcripts representing the p190 and p210 variant of BCR/ABL protein, respectively. (
  • CML cells express the oncogenic p210 BCR-ABL fusion protein, a constitutively active tyrosine kinase that stimulates multiple growth promoting signalling pathways. (
  • Here, we demonstrate that OPN expression is induced in a model of leukemia, and we describe the identification of specific signaling pathways required for the induction of OPN expression by p210 Bcr-Abl. (
  • Research data pertaining to possible cytogenetic mechanisms leading to production of p210 bcr-abl in the absence of the Ph chromosome are reviewed. (
  • Xpert BCR-ABL Ultra is a quantitative test for BCR-ABL major breakpoint (p210) transcripts that provides highly sensitive and on-demand molecular results. (
  • The product of this fusion gene, p210, a protein with deregulated tyrosine kinase activity, plays a central role in the pathogenesis of CML. (
  • The presence of this translocation is a highly sensitive test for CML, since all cases of CML are positive for BCR-ABL1 . (
  • Translocation results in an oncogenic BCR-ABL gene fusion that can be found on the shorter derivative 22 chromosome. (
  • Translocatome: a novel resource for the analysis of protein translocation between cellular organelles. (
  • protein translocation between cellular organelles. (
  • The core of the Translocatome database is the manually curated data set of 213 human translocating proteins listing the source of their experimental validation, several details of their translocation mechanism, their local compartmentalized interactome, as well as their involvement in signalling pathways and disease development. (
  • In addition, using the well-established and widely used gradient boosting machine learning tool, XGBoost, Translocatome provides translocation probability values for 13 066 human proteins identifying 1133 and 3268 high- and low-confidence translocating proteins, respectively. (
  • The database has user-friendly search options with a UniProt autocomplete quick search and advanced search for proteins filtered by their localization, UniProt identifiers, translocation likelihood or data complexity. (
  • tumor protein 63 (TP63) Translocatome allows a better comprehension of protein translocation as a systems biology phenomenon and can be used as a discovery-tool in the protein translocation field. (
  • Coarse-grained molecular dynamics study of wettability influence on protein translocation through solid nanopores. (
  • Protein translocation through nanopores is widely involved in molecular sensing and analyzing devices, whereby nanopore surface properties are crucial. (
  • Immunohistochemical pattern of c-MYC protein judged as '+/(weak)+/-' by a new notation correlates with MYC gene non-translocation in large B-cell lymphoma. (
  • The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). (
  • The cytogenetic and molecular studies showed that this chromosomal alteration involves a reciprocal translocation between chromosomes 9 and 22, resulting in a fusion gene, the BCR-ABL. (
  • Indeed, ABL/ABL translocation enhances the expression levels of the NKG2D ligands on dendritic cells, which is counteracted by imatinib mesylate. (
  • However, the effects of BCR/ABL translocation on the capacity of dendritic cells to activate NK cells have never been studied. (
  • Here we show that the BCR/ABL translocation specifically confers to dendritic cells a selective NK cell stimulatory function by up-regulating the expression of NKG2D ligands in both mouse and human models. (
  • CML is caused by one translocation that creates a singular mutation, the BCR-ABL fusion gene or Philadelphia chromosome. (
  • Leukemias with the t(9;22) translocation resulting in BCR/ABL fusion protein expression comprise 3-5% of childhood ALL. (
  • The expression of these proteins is caused by a reciprocal translocation between chromosomes, 9 and 22 in case of the BCR-ABL fusion protein . (
  • This fusion protein is generated by the Philadelphia translocation t(9;22). (
  • One of the differentiation-inducing agents, all-trans retinoic acid (ATRA), which can induce granulocytic differentiation in myeloid leukemic cell lines, has been introduced into clinics to treat patients with acute promyelocytic leukemia (APL) in which a PML-RARA fusion protein is generated by a t(15;17)(q22;q12) chromosomal translocation. (
  • Other projects directed at leukemogenic mechanisms include models of murine leukemia using inducible expression of translocation fusion proteins, such as the Bcr-Abl protein. (
  • As a result of such a chromosomal translocation the encoded fusion proteins are causing cancer. (
  • the t(9;22) translocation results in the head-to-tail fusion of BCR and ABL1, which is present in many cases of CML. (
  • This translocation results in the formation of the BCR-ABL fusion gene. (
  • BCR-ABL, a constitutively activated tyrosine kinase, is the oncogene that causes Philadelphia-chromosome-positive (Ph+) leukaemia. (
  • 9, creating the dominant oncogene BCR/abl at the junction point. (
  • This region is essential for the activation of the ABL1 tyrosine kinase and transforming potential of the chimeric BCR-ABL oncogene. (
  • HER2 is an oncogene and protein on the surface of cells that causes a cell to grow. (
  • In one mechanism, promoter/enhancer elements of one gene are rearranged adjacent to a proto-oncogene, thus causing altered expression of an oncogenic protein. (
  • The drug imatinib was developed in the 1990s by Brian Druker of Oregon Health and Science University and Charles Sawyers of Memorial Sloan Kettering to block this mutant kinase, called BCR-ABL (breakpoint cluster region - abelson murine leukemia viral oncogene homolog 1) . (
  • Numerous experimental models have established that BCR-ABL is an oncogene and is sufficient to produce CML-like disease in mice ( 9 , 10 ). (
  • The BCR-ABL oncogene is expressed at all stages, but blast crisis is characterized by multiple additional genetic and molecular changes. (
  • Sawyers pointed out that, ¿Gleevec was designed to inhibit or block the BCR-ABL oncogene. (
  • So when the drug stops working, there are two possibilities: One, it is still blocking BCR-ABL, but the cancer cell doesn¿t care because it has other oncogene signals in which to grow. (
  • [ 5 ] KIT is a member of the receptor tyrosine kinase family of proteins, a transmembrane protein encoded by the c- kit proto-oncogene. (
  • Alternatively, a proto-oncogene is fused to a strong promoter, and thereby the oncogenic function is set to function by an upregulation caused by the strong promoter of the upstream fusion partner. (
  • Some mutations create a more potent Bcr-Abl oncogene and accelerate disease progression[ 9 ]. (
  • In the cytoplasm Bcr-Abl acts as an oncogene by interacting with multiple signal transduction pathways that transmit anti-apoptotic and mitogenic signals[ 14 ]. (
  • The Abl gene expresses a membrane-associated protein, a tyrosine kinase , and the BCR-Abl transcript is also translated into a tyrosine kinase containing domains from both the BCR and ABL1 genes. (
  • E proteins activate transcription by binding to regulatory E-box sequences on target genes as heterodimers or homodimers, and are inhibited by heterodimerization with inhibitor of DNA-binding (class IV) helix-loop-helix proteins. (
  • t(1;19)(q23;p13.3) TCF3-PBX1 fusion in pre-B-cell ALL t(1;19)(q23;p13.3) translocations fusing the PBX1 and E2A genes occur in approximately a quater of paediatric pre-B cell acute lymphoblastic laeukemias. (
  • A fusion of genes creates an aberrant protein, known as BCR-ABL, which fuels uncontrolled cell growth. (
  • Bose S, Deininger M, Gora-Tybor J, Goldman JM, Melo JV (1998) The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. (
  • JAK2 V617F, or fusion genes, e.g. (
  • 2 , 3 To date, more than 35 different fusion genes have been identified in association with Eos-MPD ( Figure 1 ), the most common of which is FIP1L1-PDGFRA , generated by a cytogenetically invisible 800kb interstitial deletion on chromosome 4q12. (
  • The mission of my lab is to facilitate the discovery, validation, and implementation of candidate target genes/proteins in disease diagnosis, prognosis, and therapy. (
  • In the second mechanism, the rearrangement results in the fusion of two genes, which produces a fusion protein that may have a new function or altered activity. (
  • Similar fusion genes (and proteins) have since been found in other blood cancers but had not been detected in solid tumors, such as those affecting the breast , prostate , colon , lung , and pancreas , thyroid, kidney and brain. (
  • A fusion gene is a hybrid gene formed from two previously independent genes. (
  • Fusion genes have been found to be prevalent in all main types of human neoplasia. (
  • The identification of these fusion genes play a prominent role in being a diagnostic and prognostic marker. (
  • Fusion genes can contribute to tumor formation because fusion genes can produce much more active abnormal protein than non-fusion genes. (
  • Most fusion genes are found from hematological cancers, sarcomas, and prostate cancer.BCAM-AKT2 is a fusion gene that is specific and unique to high-grade serous ovarian cancer. (
  • Oncogenic fusion genes may lead to a gene product with a new or different function from the two fusion partners. (
  • Presence of certain chromosomal aberrations and their resulting fusion genes is commonly used within cancer diagnostics in order to set a precise diagnosis. (
  • Such gene fusions are almost exclusively between genes that encode enzymes that perform sequential steps in the biosynthetic pathway. (
  • Microarray analysis of uninfected HeLa cells following knockdown of GliPR revealed, among a multitude of gene expression alterations, a down-regulation of syndecan-1, syndecan-2, protein kinase C alpha (PRKCA), the catalytic subunit beta of cAMP-dependent protein kinase (PRKACB), nuclear receptor co-activator 3 (NCOA3), and cell surface protein CD59 (protectin), all genes having relevance for HIV-1 pathology. (
  • BCR-ABL is a mutation that is formed by the combination of two genes, known as BCR and ABL. (
  • The BCR-ABL mutation happens when pieces of BCR and ABL genes break off and switch places. (
  • Protein kinase CK2 phosphorylates PRH and counteracts the inhibitory effect of this protein on cell survival by blocking the repression of VSP genes. (
  • At a molecular level, there is rearrangement of the BCR and ABL genes with the function of codifying a fusion protein with increased and deregulated tyrosine kinase activity. (
  • Genes encoding protein kinase domains are the most frequently mutated in human cancer ( 15 ) and are tractable candidates for therapeutic intervention. (
  • In a simple vector, genes coding for viral proteins are replaced by the desired transgene. (
  • This results usually in the formation of so-called "fusion genes" that are transcribed into fusion mRNAs. (
  • Not all fusion genes lead to cancer. (
  • But in some cells, a fusion gene produces fusion proteins that can alter the activity of other genes. (
  • Many fusion oncoproteins in children, however, involve transcription factors, which are proteins that control the activity of genes by binding to DNA. (
  • Gleevec, developed by Novartis and approved in 2001, inhibits the action of that errant protein. (
  • So companies developed other drugs - Tasigna from Novartis and Sprycel from Bristol-Myers Squibb - that also inhibit the aberrant protein but work in many of the cases that are resistant to Gleevec. (
  • The assay platform was evaluated by assessing changes in a rationally selected subset of the Tyr phosphoproteome of Bcr-Abl-expressing cells treated with a specific inhibitor, Gleevec, and of epidermal growth factor (EGF)-treated HeLa cells. (
  • This finding led to the development of imatinib mesylate (Gleevec), which successfully targets the BCR-ABL kinase. (
  • The drug, named STI-571 and later renamed imatinib (Gleevec), blocks the activity of the BCR-ABL fusion protein. (
  • The small-molecule kinase inhibitor imatinib (Gleevec, Novartis) binds to the active site of the Bcr-Abl kinase domain and inhibits its constitutive tyrosine kinase activity ( 2 , 3 ). (
  • And when we treat with a drug directed against only one of them ¿ Gleevec against ABL ¿ when the cell becomes resistant, it does so by turning on BCR-ABL again, and gets around the drug by that oncogenic reaction. (
  • But possibility two,¿ he went on, ¿is that something about BCR-ABL changes itself in order to get around the drug ¿ so it can keep doing what it wants to do despite Gleevec being there. (
  • Pharmacological inhibition using the selective c-Abl kinase inhibitor Gleevec confirmed that c-Abl plays an important role in Hp pathogenesis in a murine in vivo model. (
  • STI 571 or Imatinib (Novartis)), as well as well-known follow-up inhibitors, being more potent and/or more active against the emerging Gleevec/Glivec resistant BCR-ABL clones that originate from point mutations inside the kinase domain of the Bcr-Abl protein and disrupt the binding site of Imatinib on the tyrosine kinase (e.g. (
  • Imatinib, known commercially as Gleevec and produced by Novartis Pharmaceuticals, was the first drug to target the fusion protein BCR-ABL that causes the disease. (
  • Several drugs that are effective against fusion oncoproteins have been developed, such as imatinib (Gleevec) , which blocks the activity of the BCR-ABL fusion protein . (
  • Although Gleevec is currently the "gold standard" drug of choice for Bcr-Abl-positive CML[ 3 - 5 ], resistance to treatment with Gleevec occurs. (
  • This is mostly due to mutations in the Bcr-Abl kinase domain that render it unable to bind to Gleevec[ 6 - 8 ]. (
  • Other mechanisms for resistance include Bcr-Abl amplification or overexpression, clonal evolution, a decrease in Gleevec bioavailability or cell exposure, and upregulation of drug efflux pumps[ 6 , 10 ]. (
  • They used Gleevec to stimulate Bcr-Abl to go to the nucleus (by unknown mechanism), followed by nuclear entrapment by leptomycin B (LMB), a general inhibitor of nuclear export. (
  • After washout of Gleevec, Bcr-Abl's tyrosine kinase activity is re-activated, and the cells undergo spontaneous apoptosis. (
  • Over time, some patients develop resistance to Gleevec and other drugs that block BCR-ABL, the misbegotten "fusion" protein that drives CML growth. (
  • Several different variants of the bcr-abl fusion proteins occur depending upon the precise location of the chromosomal breakpoint. (
  • The breakpoint on chromosome 9 is located in intron 1 of the abl gene locus. (
  • To date, three main breakpoint cluster regions in the BCR gene have been reported: the M - bcr region located between exons 12 and 16, the m - bcr located between exons e2′ and e2 and the u - bcr located in exon 19. (
  • The symbol BCR is derived from breakpoint cluster region, a gene which encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins. (
  • The suppression of constitutively active ABL kinase by specific kinase inhibitors, such as Imatinib [ 3 ], Nilotinib [ 4 ] and Dasatinib. (
  • We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. (
  • Although ABL kinase inhibitors have shown great promise in the treatment of CML, the persistence of residual disease and the occurrence of resistance have prompted investigations into the molecular effectors of BCR-ABL. (
  • Although highly potent kinase inhibitors, such as AMN107 ( 9 ) and BMS-354825 ( 10 ), have been recently developed to target imatinib resistance, these compounds do not inhibit all possible imatinib-resistant mutants of BCR-ABL [i.e., a commonly occurring threonine-to-isoleucine mutation at residue 315 (T315I), located within the kinase domain of BCR-ABL]. (
  • Therefore, kinase inhibitors targeting imatinib-resistant variants of Bcr-Abl have been developed. (
  • Treatment of CML has been revolutionized by the advent of specific ABL tyrosine kinase inhibitors now used in the front-line management of this disease ( 7 ). (
  • Therefore, second-generation kinase inhibitors, such as dasatinib, that effectively block the activity of most mutant forms of BCR-ABL are now being used to treat imatinib-resistant CML ( 9 , 10 ). (
  • The ABL-kinase inhibitors (AKIs) Imatinib, Nilotinib or Dasatinib, which target the ATP-binding site, are effective in Ph + leukemia. (
  • Conclusions: Our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants using a combination of AKIs and allosteric inhibitors. (
  • Targeted inhibition of BCR/ABL by small molecule inhibitors reverses the transformation potential of BCR/ABL. (
  • A small individual group of tyrosine kinase inhibitors is specifically targeting oncogenic fusion proteins. (
  • Breakthroughs to date have been made in the development of anti-angiogenesis inhibitors that target the tumor vasculature and of modulators of gene expression and protein stability, according to Courtneidge. (
  • Many more agents have been added to the pipeline of cancer drugs, including inhibitors that target the BCR-ABL fusion protein and other kinases. (
  • The researchers wanted to determine how these inhibitors that deacetylate proteins and histones affect the cell's function. (
  • Studies employing currently available highly specific inhibitors, with high potency to block kinase activity, uncovered unanticipated characteristics of Bcr-Abl fusion protein. (
  • Multiple BCR-ABL tyrosine kinase inhibitors (TKIs) are approved, and are the standard of care for CML. (
  • Many other tyrosine kinase inhibitors (TKIs) are being studied and developed, with a few already approved nonetheless, Bcr-Abl also has the potential to develop resistance to these molecules. (
  • Tyrosine kinase inhibitor (TKI) therapy with small molecule inhibitors of BCR-ABL tyrosine kinase has significantly reduced the annual mortality rate among patients with CML. (
  • Imatinib mesylate binds to the inactive conformation of BCR-ABL tyrosine kinase suppressing the Philadelphia chromosome positive clone in CML. (
  • After the Philadelphia chromosome mutation and defective bcr-abl protein were discovered, researchers screened chemical libraries to find a drug that would inhibit that protein. (
  • In May of 2001, imatinib was approved by the FDA for the initial therapy for CML and later, Philadelphia chromosome (Ph)- positive acute lymphoblastic leukemia (ALL), by targeting the bcr-ablprotein, preventing further development of leukemia cells. (
  • The discovery of the Philadelphia chromosome and BCR-ABL, supported in part by NCI, demonstrated for the first time that a genetic alteration could cause cancer. (
  • BCR-ABL1 gene An abnormal gene that is formed when the BCR gene and ABL gene join together on the Philadelphia chromosome. (
  • One of the theories concerning Imatinib resistance was the elevated expression of SCR and the loss of function due to the "Philadelphia chromosome" in BCR and ABL proteins. (
  • The BCR/ABL fusion protein is the hallmark of Philadelphia Chromosome positive (Ph+) leukemia. (
  • Surprisingly, BCR-ABL transcripts are also present in healthy people who do not have the Philadelphia chromosome. (
  • CML occurs with the overproduction of white blood cells caused by the Philadelphia chromosome, in which swapped DNA creates a mutant fusion bcr-abl protein that drives the disease. (
  • Patients with MDS/MPN do not have a Philadelphia chromosome or BCR/ABL fusion gene. (
  • This gene encodes for a BCR-ABL fusion protein. (
  • This gene encodes a transcription factor that belongs to the family of zinc-finger DNA-binding proteins associated with chromatin remodeling. (
  • This gene encodes a member of the E protein (class I) family of helix-loop-helix transcription factors. (
  • As a result the BCR/ABL fusion gene is formed which encodes a specific mRNA, translated into BCR/ABL proteins with an abnormally high tyrosine kinase activity, playing a crucial role in leukemic transformation and neoplastic proliferation of hematopoietic stem cells. (
  • The BCR-ABL fusion gene encodes a constitutively active leukemogenic protein tyrosine kinase [ 9 ]. (
  • The resulting BCR-ABL fusion gene encodes a cytoplasmic protein with constitutive tyrosine kinase activity ( 8 ). (
  • In a 1979 paper in the journal Cell, they described their findings that phosphate in cell culture was associated with one of the three proteins the virus encodes to transform normal cells into tumor cells. (
  • A gene on chromosome 9q34.1 that encodes a cytoplasmic and nuclear protein tyrosine kinase involved in cell differentiation, cell division, cell adhesion and stress response. (
  • Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease. (
  • Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. (
  • The bar plot below shows the proportion of tumor samples that have any kind of altering mutation(s) in the given protein. (
  • Dasatinib inhibits Bcr-Abl kinase activity in the low-nanomolar range and inhibits all clinically relevant imatinib-resistant forms with the exception of the common T315I (gatekeeper) mutation ( 12 , 14 ). (
  • Now, via a fast-track electronic release, Science reports in its issue dated June 21, 2001: ¿Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. (
  • The Dasatinib ABL inhibitor has demonstrated effective inhibition of nearly all the BCR-ABL mutations, the exception being T3151 mutation. (
  • Given the fact that all AKIs fail to inhibit BCR/ABL harboring the 'gatekeeper' mutation T315I, we investigated the effects of AKIs in combination with the allosteric inhibitor GNF2 in Ph + leukemia. (
  • A BCR-ABL genetic test looks for a genetic mutation (change) on a specific chromosome. (
  • The BCR-ABL gene is not the type of mutation that is inherited from your parents. (
  • Certain cancer medicines are especially effective in treating leukemia patients with the BCR-ABL gene mutation. (
  • As a constitutively active tyrosine kinase, BCR-ABL induces the hyperactivation of various signaling pathways that promote cell growth and suppress apoptosis, ultimately resulting in leukemogenesis ( 2 , 4 ). (
  • Vigneri and Wang have previously shown that nuclear entrapment of Bcr-Abl in K562 cells results in apoptosis, and requires an active tyrosine kinase domain to do so[ 2 ]. (
  • Inhibition of Bcr-Abl kinase by STI571 results in FoxO3a activation, induction of Bim expression and apoptosis. (
  • Bortezomib treatment led to inhibition of BCR-ABL-induced suppression of FoxO proteins and their proapoptotic targets, tumor necrosis factor-related apoptosis-inducing ligand and BIM, thereby providing novel insights into the molecular effects of proteasome inhibitor therapy. (
  • The concentration that produced 50% inhibition (IC 50 ) for these effects was approximately 100 nmol/L, which is similar to the concentration required for inhibition of bcr-abl and PDGFR. (
  • Dasatinib is a dual ABL-Src kinase inhibitor that exhibits a more potent but less selective inhibition of BCR-ABL than imatinib and is commonly used in treatment of imatinib resistant CML. (
  • The activity of tyrosine kinases is typically regulated in an auto-inhibitory fashion, but the BCR-Abl fusion gene codes for a protein that is "always on" or constitutively activated, leading to impaired DNA binding and unregulated cell division (i.e. cancer). (
  • [10] Although the BCR region also expresses serine/threonine kinases, the tyrosine kinase function is very relevant for drug therapy. (
  • Superti-Furga, G. & Courtneidge, S.A. Structure-function relationships in Src family and related protein tyrosine kinases. (
  • First, chemical or genetic modifications are often required, such as generating fusion proteins or adding chemical linkers to the inhibitor, which may change the binding properties of the kinases and the inhibitor compounds. (
  • We have analyzed the kinases targeted by dasatinib by using an unbiased chemical proteomics approach to detect binding proteins directly from lysates of CML cells. (
  • Besides Abl and Src kinases, we have identified the Tec kinases Btk and Tec, but not Itk, as major binders of dasatinib. (
  • Imatinib is a relatively weak inhibitor of Bcr-Abl, with an IC 50 in the upper nanomolar range, but has remarkable specificity, targeting only particular conformations of very few other kinases, mainly Abl family members, c-Kit and PDGF-R ( 5 - 8 ). (
  • Dasatinib has been developed as a Src/Abl inhibitor but subsequently has been shown to affect a wider array of kinases ( 11 ). (
  • In addition, dasatinib has recently been used in a drug-target profiling approach by using a library of ≈150 selected recombinant kinases expressed as phage particle fusion proteins, of which 67 were bound by dasatinib ( 15 ). (
  • Tec kinases are the second largest group of nonreceptor tyrosine kinases and are closely related to the Src and Abl kinases ( 21 , 22 ). (
  • This led Hunter to generate sequence alignments of the viral tyrosine kinase proteins, as well as protein kinases that phosphorylate serine and threonine, which revealed that the catalytic domain of tyrosine kinase has a series of conserved short sequence motifs that are essential for transferring phosphate. (
  • STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. (
  • STI 571 (formerly known as CGP 57148B), a 2-phenylaminopyrimidine derivative, is a known inhibitor of the c-abl, bcr-abl, and PDGF receptor (PDGFR) tyrosine kinases. (
  • Evidence that has accumulated over the last years points to c-Abl and Arg (ABL1 and ABL2) as being particular forms of the Src family of kinases. (
  • Just as much as or even more than the Src kinases, Abl members are built to be able to couple protein-protein interaction with protein tyrosine kinase catalytic output. (
  • The Abl family of tyrosine kinases is regulated by a complex set of intramolecular interactions that impinge both directly and indirectly on the Abl kinase domain and lead to effective inhibition of tyrosine kinase activity both in vitro and in vivo. (
  • On the other hand, the controlled activation of Abl kinases is required for a large number of normal cellular processes. (
  • In this chapter, we provide an overview of the mechanisms by which multiple cellular proteins transiently activate Abl kinases to perform cellular functions. (
  • Hantschel O, Superti-Furga G. Regulation of the c-Abl and Bcr-Abl Tyrosine Kinases. (
  • Pendergast AM. The Abl family kinases: Mechanisms of regulation and signaling. (
  • Pfizers Bosulif (bosutinib) is a second-generation TKI that inhibits BCR-ABL, as well as SRC-family kinases (Bosulif Prescribing Information, 2012). (
  • Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. (
  • In this study, we have used the human BV173 and the mouse BaF3/Bcr-Abl-expressing cell lines as model systems to investigate the molecular mechanisms whereby STI571 and FoxO3a regulate Bim expression and apoptosis. (
  • Conversely, silencing of FoxO3a in Bcr-Abl-expressing cells abolishes STI571-mediated Bim induction and apoptosis. (
  • Figure 2: GNF-2 blocks proliferation and induces apoptosis of Ba/F3 cells expressing wild-type Bcr-abl and the E255V mutant. (
  • An engineered Abl SH2-binding fibronectin type III monobody inhibited Bcr-Abl kinase activity both in vitro and in primary CML cells, where it induced apoptosis. (
  • It has been shown that imatinib blocks the cells proliferation and induces apoptosis in BCR-ABL expressing hematopoietic cells. (
  • Our data delineate the involvement of FoxO proteins in BCR-ABL-induced evasion of apoptosis and provide evidence that bortezomib is a candidate therapeutic in the treatment of BCR-ABL-induced leukemia. (
  • Mislocalization of tumor suppressors, oncogenes, or factors involved in apoptosis result in aberrant functioning of these proteins, leading to disease. (
  • On the other hand, nuclear entrapment of endogenous Bcr-Abl (in K562 human leukemia cells) causes apoptosis. (
  • The goal of this study was to determine whether plasmid expressed Bcr-Abl could cause apoptosis of K562 cells when specifically directed to the nucleus via strong nuclear localization signals (NLSs). (
  • Apoptosis induced by 4NLS-Bcr-Abl was evaluated 24 hours post-transfection by morphologic determination, DNA staining, and caspase-3 assay. (
  • Multiple NLSs are required to overcome Bcr-Abl binding to actin, thus driving it into the nucleus and causing apoptosis. (
  • In the nucleus, Bcr-Abl may cause apoptosis due to nuclear Abl's ability to stabilize p73 and activate its pro-apoptotic functions. (
  • Resistance may occur at the level of Bcr-Abl, with reduction or loss of imatinib effectiveness as a kinase inhibitor, or, despite retention of its inhibitory ability, with changes in the ability to deliver an effective dose at the cellular level, and/or, the leukemia becoming less dependent on Bcr-Abl. (
  • Acute lymphoblastic leukemia with e1a3 BCR/ABL fusion protein. (
  • The symbol ABL is derived from Abelson , the name of a leukemia virus which carries a similar protein. (
  • The bcr-abl gene is constitutively active (meaning it does not require activation by other proteins), and sends signals to activate proteins and enzymes which speed up cellular division and can lead to the formation of abnormal white blood cells that proliferate to the point that they interfere with normal blood cell production, leading to leukemia. (
  • CINCINNATI - Scientists identify two signaling proteins in cancer cells that make them resistant to chemotherapy, and show that blocking the proteins along with chemotherapy eliminate human leukemia in mouse models. (
  • Reporting results March 20 in Nature Medicine , researchers at Cincinnati Children's Hospital Medical Center suggest that blocking the signaling proteins c-Fos and Dusp1 as part of combination therapy might cure several types of kinase-driven, treatment-resistant leukemia and solid tumor cancers. (
  • Of these, only dasatinib (Sprycel, BMS-354825, Bristol-Myers Squibb) has so far been approved for the treatment of adults with CML and Bcr-Abl-positive acute lymphocytic leukemia with imatinib resistance or intolerance to previous therapy ( 11 - 13 ). (
  • To characterize the mechanism of relapse in STI-571-treated patients, we first assessed the status of BCR-ABL signaling in primary leukemia cells ( 12 ). (
  • If BCR-ABL remains critical for the proliferation of the leukemia clone, then the BCR-ABL signaling pathway should be reactivated. (
  • Alternatively, if the expansion of the leukemia clone is independent of BCR-ABL, then signaling through the BCR-ABL pathway should remain impaired by STI-571. (
  • We¿ve known for years that BCR-ABL initiates the first hit in the development of this leukemia. (
  • Deregulated c-Abl activity has been intensively studied in a variety of solid tumors and leukemia. (
  • Recently, we definitively proved that targeting the tetramerization of BCR/ABL mediated by the N-terminal coiled-coil domain (CC) using competitive peptides, representing the helix-2 of the CC, represents a valid therapeutic approach for treating Ph+ leukemia. (
  • The BCR-ABL gene shows up in patients with certain types of leukemia , a cancer of the bone marrow and white blood cells. (
  • The BCR-ABL gene is also found in some patients with a form of acute lymphoblastic leukemia (ALL) and rarely in patients with acute myelogenous leukemia (AML). (
  • Although originally described as a tumor suppressor gene, the WT1 protein also seems to be involved in tumorigenesis, as WT1 expression is up-regulated in leukemia cells of all lineages ( 2 , 3 ) and in several solid tumors, including malignant mesothelioma, lung, breast, prostate, and ovarian carcinomas ( 4 ). (
  • It became apparent that the kinase domain, with its primary significance for development and progression of leukemia, is not solely responsible for leukemogenic features of the Bcr-Abl transformed leukemic stem cells. (
  • This is the first demonstration that altering the location of plasmid expressed Bcr-Abl can kill leukemia cells. (
  • Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) of fusion gene transcripts for residual disease detection in leukemia - A Europe Against Cancer Program: Leukemia. (
  • Fusion between M-bcr and abl results in the 'small' abl/bcr fusion gene encoding a 'small' ABL/BCR transcript, detectable in 65% patients suffering from CML [ 6 ], which is translated into an ABL/BCR protein with a theoretical molecular mass of about 40 kDa - p40 (ABL/BCR) (Zheng et al. (
  • We report two new cases of B-ALL Ph+ with the rare e1a3 fusion transcript. (
  • The presence of BCR/ABL fusion gene offers a possibility of the fusion transcript detection - a faster and cheaper alternative to Ig/TCR-based MRD monitoring. (
  • When GliPR was suppressed by siRNA, HIV-1 replication was significantly reduced as measured by HIV-1 transcript levels, HIV-1 p24 protein levels, and HIV-1 LTR-driven reporter gene expression, suggesting that GliPR is a cellular co-factor of HIV-1. (
  • Her BCR-ABL1 fusion transcript was more than 0.1% after 1 year of treatment, and thus, her treatment was changed to nilotinib 400 mg twice daily, as a second-line TKI. (
  • She was compliant with medication and showed a good response with her BCR-ABL1 transcript dropping to less than 0.1% after 3 months of therapy. (
  • Currently, assessing treatment efficacy for CML requires a molecular diagnostic assay to measure the level of BCR-ABL transcript (RNA). (
  • STI571, a competitive inhibitor at the ATP-binding site of BCR-ABL, has been shown to have high activity in this type of leukaemia. (
  • Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. (
  • Overriding imatinib resistance with a novel ABL kinase inhibitor. (
  • Ponatinib is a tyrosine kinase inhibitor, targeting the BCR-ABL fusion proteins. (
  • Alternative strategies, such as Aurora kinase inhibitor, VX680, which also targets ABL, as well as combination therapies using chemotherapeutic agents and imatinib have shown some success in the treatment of the T315I mutant ( 11 , 12 ). (
  • Targeting heat shock response protein with panobinostat, combined with an autophagy inhibitor, is an effective treatment strategy against growing stress cells in breast cancer. (
  • Here we show that the BCR-ABL/Src kinase inhibitor dasatinib decreases PRH phosphorylation and increases PRH-dependent repression of Vegf and Vegfr-1. (
  • Managing CML in most diagnosed patients is achieved by oral administration of a Tyrosine Kinase Inhibitor (TKI) that specifically targets the activity of the BCR-ABL fusion protein. (
  • Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. (
  • Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain. (
  • Pre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. (
  • After a median follow-up of 30 months (range 8-48), all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. (
  • allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. (
  • All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. (
  • In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. (
  • We aimed to find out whether point mutations in BCR-ABL cause resistance to STI571. (
  • We analysed clinical samples from eight patients resistant to STI571-who had advanced-stage Ph+ leukaemia-for mutations within the ATP-binding site and activation loop of BCR-ABL. (
  • We identified five distinct point mutations in the BCR-ABL kinase domain in seven patients. (
  • Different mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. (
  • Scope includes mutations and abnormal protein expression. (
  • Whereas clinical data from imatinib treatment seem promising, the development of resistance due to primary or acquired point mutations in BCR-ABL ( 7 , 8 ) is a growing problem. (
  • Third, cancer cells are notoriously known to evolve point mutations or to activate alternative signaling proteins to escape drug inhibition ( 13 , 14 ). (
  • Resistance is predominantly caused by point mutations in the kinase domain of Bcr-Abl ( 9 , 10 ). (
  • This drug resistance is most often due to selection for secondary mutations in the BCR-ABL oncoprotein, rather than to "downstream" mutations affecting the signaling pathways subverted by the BCR-ABL kinase ( 8 ). (
  • Very rarely, familial disorders associated with underlying mutations of the KIT protein result in GIST oncogenesis. (
  • Approximately 90% of metastatic GISTs have been reported to have mutations of the KIT protein, and more than 80% of morphologically benign GISTs also harbor KIT mutations. (
  • Indeed, RNAs not coding for proteins occur in cells in great numbers, and errors that occur during the process of transcription may lead to rare RNAs molecules carrying different types of mutations. (
  • In addition to the proximal effects on ABL and its immediate targets, dasatinib broadly affected the downstream MAPK pathways. (
  • We immobilized dasatinib and used the resultant resin as an affinity reagent to identify binding proteins from cell lysates by SDS/PAGE and liquid chromatography coupled to tandem MS (LC-MSMS). (
  • ABL - 3 nM, BCR - 3nM for purified protein) [6].The design was successful and Dasatinib mechanism of action demonstrates efficacy of approximately 300 times more compared to Imatinib [7]. (
  • Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner. (
  • Patients taking dasatinib achieve complete cytogenetic response - absence of the mutated protein that drives this disease - more rapidly than we ve observed historically using the current front-line therapy. (
  • Atallah explains that dasatinib binds to both forms BCR-ABL while imatinib blocks only one. (
  • The CML therapeutic imatinib and its derivative dasatinib inhibit the tyrosine kinase activity of BCR-ABL resulting in leukaemic cell death. (
  • The constitutively activated BCR/ABL-kinase 'escapes' the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. (
  • Presently, the majority of tumor biomarkers are proteins or peptides. (
  • Here, we show that BCR-ABL stimulates the proteasome-dependent degradation of members of the forkhead family of tumor suppressors in vitro , in an in vivo animal model, and in samples from patients with BCR-ABL-positive CML or ALL. (
  • But in 2005 Arul Chinnaiyan at the University of Michigan found the first gene fusions in a solid tumor, in prostate tumors [1]. (
  • Wilms' tumor 1 protein (WT1), a transcription factor overexpressed in malignant mesothelioma, leukemias, and other solid tumors, is an ideal target for immunotherapy. (
  • Wilms' tumor 1 protein (WT1) is a zinc finger transcription factor that is normally expressed in tissues of the mesodermal origin during embryogenesis, including the kidney, gonads, heart, mesothelium, and spleen. (
  • Expression of WT1 ( 11 ) and immunohistochemical detection of the WT1 protein ( 12 ) have been observed in most mesothelioma cell lines and primary tumor specimens, and WT1 expression is currently used as a diagnostic marker to distinguish mesothelioma from similar tumors, such as pulmonary adenocarcinoma ( 12 ). (
  • They identify and characterize a role for the CHCHD4 mitochondrial proteins in regulating HIF-α signaling, angiogenesis, and tumor progression. (
  • Through biochemical and molecular analysis of clinical material, we find that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined. (
  • In six of nine patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. (
  • In three patients, resistance was associated with progressive BCR-ABL gene amplification. (
  • However, patients with the translocated gene demonstrate resistance to Imatinib due in part to the nature of fused BCR-ABL gene [4]. (
  • In an effort to overcome this resistance a molecule similar to Imatinib was designed and screened for activity against this fusion protein. (
  • In this review we summarize current understanding of non-enzymatic characteristics of Bcr-Abl, its effect on actin cytoskeleton, and its potential contribution to drug resistance and systemic persistence of leukemic stem cells. (
  • Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1. (
  • The fused BCR-ABL protein interacts with the interleukin-3 receptor beta(c) subunit and is moderated by an activation loop within its SH1 domain, which is turned "on" when bound to ATP and triggers downstream pathways. (
  • Regulation of the regulator of G protein signaling 2 expression and cellular localization by PKA and PKC pathways in mouse granulosa cells. (
  • G protein-coupled receptor (GPCR) activation-mediated PKA and PKC pathways have been recognized to be important in ovarian physiology. (
  • As an alternative to targeting the ABL kinase, a promising approach involves the inhibition of downstream cellular pathways critical for BCR-ABL-mediated leukemogenesis. (
  • Although our results indicate that a diversity of genetic changes are seen at relapse, integration of gene expression, CNA, and methylation data suggest a possible convergence on the WNT and mitogen-activated protein kinase pathways. (
  • This integrated analysis, of 3 high throughput platforms, suggests that although multiple defects evolve from diagnosis to relapse, some may converge on distinct pathways, such as the WNT and mitogen-activated protein kinase signaling pathways. (
  • Here, we investigated the activity and subcellular localization of c-Abl in vitro and in vivo and unraveled the contribution of c-Abl in CagA-dependent and -independent pathways to gastric Hp pathogenesis. (
  • A major distinctive feature of the purine biosynthetic pathways in Bacteria is the prevalence of gene fusions where two or more purine biosynthetic enzymes are encoded by a single gene. (
  • This research spans studies on the genetic makeup of cancer cells, validation studies on the roles of key signaling proteins and pathways, the development of novel agents, and the testing of those agents in a variety of pre-clinical and clinical settings," Courtneidge added. (
  • In CML patients, between 73% and 100% of monocyte-derived dendritic cells (CML dendritic cells) are positive for the chimeric ABL/ABL gene ( 19 , 20 ). (
  • 8) Cepheid Xpert BCR-ABL Ultra Package Insert 301-2194. (
  • Based on the innovative GeneXpert technology, Xpert BCR-ABL Ultra automates the entire test process including RNA isolation, reverse transcription, and fully nested real-time PCR of BCR-ABL target gene and ABL reference gene in one fully automated cartridge. (
  • Furthermore, disruption of the SH2-kinase interface increased sensitivity of imatinib-resistant Bcr-Abl mutants to TKI inhibition. (
  • We additionally show sensitivity of imatinib-resistant BCR-ABL T315I cells to bortezomib. (
  • The class-I carcinogen Helicobacter pylori ( Hp ) activates the non-receptor tyrosine kinase c-Abl to phosphorylate the oncoprotein cytotoxin-associated gene A (CagA). (
  • The resulting Bcr-Abl fusion protein acts as an oncoprotein, and the constitutive activation of tyrosine kinase activity of Abl leads to cell proliferation. (
  • BCR-ABL , generated by chromosomal translocations, insertions or deletions. (
  • Since chromosomal translocations play such a significant role in neoplasia, a specialized database of chromosomal aberrations and gene fusions in cancer has been created. (
  • It remains unclear why this is the case, but they have identified in healthy cells all types of fusion RNA transcripts that are know from chromosomal translocations. (
  • additionally, the ERK pathway can be activated by fusion proteins resulting from chromosomal translocations such as BCR-ABL. (
  • We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism. (
  • Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis. (
  • These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. (
  • Inhibits the apoptotic signals regulated by the Bcl-2 family proteins through the formation of a Nef/PI3-kinase/PAK2 complex that leads to activation of PAK2 and induces phosphorylation of Bad (By similarity). (
  • When a cancer has extra HER2 protein, it's called HER2 overexpression or a HER2-positive cancer. (
  • Some types of cancer have a mutated HER2 gene that makes extra HER2 proteins and causes the cancer to grow. (
  • Such solid tumors account for 80% of cancer deaths in the U.S. Some researchers thought that there were no fusions in solid tumors, while others thought they might be there but were more difficult to find because of the many chromosomal defects in these cancers. (
  • Interestingly, most of the patients with the ALK fusions were non-smokers and their cancers were adenocarcinomas (meaning a cancer of epithelial tissue). (
  • If five percent of all patients with non-small cell lung cancer end up being positive for an ALK fusion, as suggested by the study of Kwak et al. (
  • Researchers report March 20 in Nature Medicine that two signaling proteins in certain cancer cells make them. (
  • CML is a blood cancer driven by an enzyme called tyrosine kinase, which is formed by the fusion gene BCR-ABL. (
  • Azam and colleagues show in their CML models that signaling from tyrosine kinase - and growth factor proteins that support cell expansion (like interleukins IL3, IL6, etc.) - converge to dramatically elevate c-Fos and Dusp1 levels in the cancer cells. (
  • The first fusion gene was described in cancer cells in the early 1980s. (
  • In the case of TMPRSS2-ERG, by disrupting androgen receptor (AR) signaling and inhibiting AR expression by oncogenic ETS transcription factor, the fusion product regulates the prostate cancer. (
  • This database is called Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. (
  • Bhalla and colleagues evaluated the stress phenotype of breast cancer cells in the mammary fat pad of mice when mediated by two heat shock proteins - hsp90 and hsp70, which help to promote cancer survival. (
  • [1] [2] Note=Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation. (
  • In this study, we analyzed the prognostic value of epithelial membrane protein 3 (EMP3) in terms of overall survival (OS) in glioblastoma multiforme (GBM) and the association between its expression and DNA methylation.Bioinformatic analysis was performed by using data from the Cancer Genome Atlas (TCGA) database.EMP3 expression was markedly higher in GBM tissues than in normal brain tissues. (
  • Researchers supported by the Cancer Moonshot initiative are studying the role of fusion proteins in childhood cancers. (
  • The goal of the consortium is to bring together experts who have different skills and perspectives to think about fusion proteins in new ways," said Keren Witkin, Ph.D., of NCI's Division of Cancer Biology , who coordinates the group. (
  • Researchers participating in the consortium-which is part of the Cancer Moonshot℠ initiative to accelerate progress in cancer research-are investigating various cancers driven by fusion proteins in children and young adults. (
  • Chromosome breaks leading to fusion oncoproteins are very common in childhood cancers," said Kimberly Stegmaier, M.D., of the Dana-Farber Cancer Institute, who is leading one of the research teams. (
  • In theory, Dr. Witkin said, "fusion oncoproteins are terrific drug targets, because they drive the disease and are present only in cancer cells. (
  • For the pediatric cancer field, the holy grail has been to find a way to directly target the fusions that involve transcription factors," said Dr. Stegmaier. (
  • In new research that could suggest a road to cure, scientists at Dana-Farber Cancer Institute and Boston Children's Hospital have found that CML stem cells die in response to inhibition of a protein called Ezh2. (
  • As the N-terminal Y177 and CC domains from BCR encode the constitutive activation of the ABL1 kinase, these regions are targeted in therapies to downregulate BCR-ABL kinase activity. (
  • BCR-ABL1 kinase: hunting an elusive target with new weapons. (
  • Also called BCR-ABL1 fusion gene. (
  • BCR-ABL1 protein An abnormal protein that is made by the BCR-ABL1 fusion gene and causes too many abnormal white blood cells to be made. (
  • The importance of monitoring BCR-ABL1 level and response milestones, adherence to imatinib therapy, and the common adverse effects of imatinib (eg, edema, diarrhea, muscle aches) were discussed with the patient. (
  • pAbl T735 interacted with 14-3-3 proteins, which caused cytoplasmic retention of c-Abl, where it potentiated Hp -mediated cell elongation and migration. (
  • Mediates internalization and degradation of host CD4 through the interaction of with the cytoplasmic tail of CD4, the recruitment of AP-2 (clathrin adapter protein complex 2), internalization through clathrin coated pits, and subsequent transport to endosomes and lysosomes for degradation. (
  • Nevertheless, the finding of a chromosomal rearrangement is very helpful in indicating the likely presence of the underlying fusion gene and facilitating its identification. (
  • Here we show that both ABL/BCRs lost fundamental functional features of BCR regarding the regulation of small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells. (
  • FoxO3a lies downstream of Bcr-Abl signalling and is constitutively phosphorylated in the Bcr-Abl-positive BV173 and BaF3/Bcr-Abl cells. (
  • Jun proteins modulate the ovary-specific promoter of aromatase gene in ovarian granulosa cells via a. (
  • Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. (
  • PTPROt inactivates the oncogenic fusion protein BCR/ABL and suppresses transformation of K562 cells. (
  • B) HEK293 cells were transiently transfected with Bcr-Abl WT, I164E, T231R, or I164E/T231R. (
  • B) Bcr-Abl WT and I164E constructs were coexpressed with HA-tagged paxillin in HEK293 cells, and total protein extracts were analyzed by immunoblotting using the indicated antibodies. (
  • Biernaux C, Loos M, Sels A, Huez G, Stryckmans P (1995) Detection of major BCR-ABL gene expression at a very low level in blood cells of some healthy individuals. (
  • Altogether, the clonal ABL/ABL dendritic cells display the unique and selective ability to activate NK cells and may participate in the NK cell control of CML. (
  • The ABL/ABL transgene in CD34 + DR + cells causes abnormal NK cell differentiation ( 8 , 9 ). (
  • Interestingly, significant numbers of NK cells from advanced-phase CML patients are ABL/ABL + whereas T cells remain negative regardless of the disease stage. (
  • 10 ) have recently shown that ABL/ABL directly alters the function of NK cells (i.e., induces partial IL-2 independent growth and increases killer immunoglobulin-like receptor expression in primary CD56 bright NK cell subsets). (
  • Reversible protein phosphorylation is a key regulatory process in all living cells. (
  • The optimized protocol allowed detection of changes in the Tyr phosphorylation state of selected proteins using submicrogram to low nanogram of total protein extract, amounts that may conceivably be obtained from a thousand to a hundred thousand cells, or less, depending on the cell or tissue type. (
  • A 190-kilodalton phosphoprotein that is a candidate for the normal bcr protein was identified in both HeLa and K562 cells. (
  • The mutated kinase is a hybrid formed from two halves of different proteins that is created when pieces of chromosome 9 and 12 switch segments in white blood cells. (
  • Analysis of human CML cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive chemotherapy resistant cells. (
  • Owen Witte, M.D., and his colleagues at the University of California, Los Angeles, later proved that when BCR-ABL forms in blood cells, it causes CML. (
  • He reasoned that because healthy cells do not have BCR-ABL, they should not be affected by such a treatment. (
  • When mouse bone marrow cells expressing Bcr-Abl are placed in short-term cultures selectively designed to support the outgrowth of pre-B cells, only those lacking one or two Arf alleles can initiate lympholeukemias when inoculated into immunocompetent, syngeneic recipient mice. (
  • Although cells expressing the Bcr-Abl kinase can proliferate in the absence of IL-7, they remain responsive to this cytokine, which can reduce their sensitivity to imatinib. (
  • In a search for alternative measures of BCR-ABL kinase activity, we found that the phosphotyrosine content of Crkl, an adaptor protein that is specifically and constitutively phosphorylated by BCR-ABL in CML cells ( 16-18 ), could be measured reproducibly and quantitatively in clinical specimens. (
  • In this study, we identified a novel regulatory mechanism in Hp -infected gastric epithelial cells by which Hp determines the subcellular localization of activated c-Abl to control Hp -mediated EMT-like processes while decreasing cell death. (
  • Methods: The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC) from Ph + ALL-patients. (
  • The constitutive activation of the ABL-kinase in BCR/ABL cells induces the leukemic phenotype. (
  • Background: Previously, we showed that glioma pathogenesis related protein (GliPR) is induced in CEM T cells upon HIV-1 infection in vitro. (
  • Adrian Bartos and Patrycja M. Dubielecka, "The Emerging Role of Bcr-Abl-Induced Cystoskeletal Remodeling in Systemic Persistence of Leukemic Stem Cells", Current Drug Delivery (2014) 11: 582. (
  • The cells have also been profiled more extensively at the DNA, RNA, protein, chromosomal, and functional levels than any other set of cells ( 7 ). (
  • Fusion proteins occur in cells in which a piece of one chromosome breaks off and attaches to another chromosome. (
  • When transfected into K562 cells, only 4NLS-Bcr-Abl translocated to the nucleus. (
  • The stem cells' dependence on Ezh2 suggests they will be especially vulnerable to drugs that target the protein," Orkin remarks. (
  • Substances such as proteins and peptides can be readily measured and are therefore often times used as biomarkers. (
  • To further develop competitive peptides for targeting BCR/ABL, we created a membrane permeable helix-2 peptide (MPH-2) by fusing the helix-2 peptide with a peptide transduction tag. (
  • This study provides the first evidence that an efficient peptide transduction system facilitates the employment of competitive peptides to target the oligomerization interface of BCR/ABL in vivo. (
  • This is due to the replacement of the myristoylated cap region, which when present induces a conformational change rendering the kinase domain inactive, with a truncated portion of the BCR protein. (
  • The results, ratiometric rather than strictly quantitative in nature, conformed with previous identifications of several Bcr-Abl and EGF receptor targets, and associated proteins, as detected by exhaustive mass spectrometric analyses. (
  • STI-571 is a 2-phenylamino pyrimidine that targets the adenosine triphosphate (ATP) binding site of the kinase domain of ABL ( 11 ). (
  • Oncogenic fusion transcripts may also be caused by trans-splicing or read-through events. (
  • It is associated with an oncogenic fusion gene BCR-ABL, encoding a protein with tyrosine kinase activity. (
  • The fact that BCR contains Rho-GEF and Rac-GAP functions strongly suggest an important role in cytoskeleton modeling by regulating the activity of Rho-like GTPases, such as Rho, Rac and cdc42. (
  • Figure 3: Construct-dependent inhibition of abl activity by GNF-2. (
  • Deletion of this gene or diminished activity of the encoded protein may play a role in lymphoid malignancies. (
  • Phosphorylated by FES/FPS on tyrosine residues, leading to down-regulation of the BCR kinase activity. (
  • Here, we show that an intramolecular interaction between the SH2 and kinase domains in Bcr-Abl is both necessary and sufficient for high catalytic activity of the enzyme. (
  • C) Abl immunoprecipitates were assayed for catalytic activity using an optimal Abl substrate peptide, and total autophosphorylation was quantified. (
  • Kinase activity and autophosphorylation of Bcr-Abl WT were set to 1. (
  • A) Immunoprecipitated Bcr-Abl WT and I164E proteins were assayed for catalytic activity in the presence of the indicated concentrations of an optimal Abl substrate peptide containing a single tyrosine phosphorylation site. (
  • BCR-ABL kinase activity is inhibited by the selective activity of imatinib, a target agent that has demonstrated remarkable efficacy and tolerability. (
  • The vast majority of partners contain one or more dimerization domains that are required for the transforming activity of the fusion proteins. (
  • Of note, FIP1L1 does not contain any self-association motifs and it was shown that the FIP1L1 moiety is dispensable for the transforming activity of the truncated PDGFRA protein. (
  • Both proteins encode a constitutive tyrosine-specific protein kinase activity that is essential for cell transformation ( 4 , 6 ). (
  • The most direct measure of signaling through the BCR-ABL pathway is through the enzymatic activity of BCR-ABL protein itself ( 8 , 13 , 14 ). (
  • Therapeutic approaches target the VEGF ligand (bevacizumab (anti-VEGF monoclonal antibody), aflibercept (VEGF Trap)) or the tyrosine kinase receptor [sunitinib, sorafenib, and pazopanib] TKI interfere with the activity of VEGFR and other growth factors, among them PDGF receptors (PDGFRs), stem cell factor receptor (c-kit), FMS-like tyrosine kinase-3 (Flt-3), and b-raf and Bcl-Abl. (
  • They quickly followed it with another paper in the Proceedings of the National Academy of Sciences wherein they reported finding that v-SRC, the transforming protein of a second oncovirus, has kinase activity. (
  • Studies have shown that this protein is related to the protein kinase super family and has serine / threonine kinase activity, it also has phosphorylation activity for the cytoskeletal enzyme p21 Rac (Cdc42) [3]. (
  • Barilá D, Superti-Furga G. An intramolecular SH3-domain interaction regulates c-Abl activity. (
  • Arul Chinnaiyan is searching for gene fusions that drive the formation of solid tumors, with the ultimate goal of improving the early diagnosis and therapy of common cancers. (
  • Total protein extracts (left panels) and Abl immunoprecipitates (right panels) were analyzed by immunoblotting using the indicated antibodies. (
  • Search, Find and Buy Antibodies, ELISA Kits and Proteins. (
  • The ABL/BCRs are N-terminally truncated BCR mutants. (
  • However, because these strategies also target the ABL kinase, a genetic pressure may promote the emergence of additional resistant mutants. (
  • The activation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway plays a significant role in BCR-ABL-mediated leukemogenesis ( 14 ). (
  • Here, we describe and evaluate a prototype antibody (Ab) microarray platform to monitor changes in protein Tyr phosphorylation. (
  • Tyrosine phosphorylation is the least abundant post-translational modification (PTM) 1 compared with phospho-serine (p-Ser) or -threonine (p-Thr) and is estimated to be less than 0.05% of the total cellular protein phospho-amino acid content ( 12 ). (
  • c-Abl phosphorylation and localization were analyzed by immunostaining and immunofluorescence. (
  • We report a novel mechanism and identified strong c-Abl threonine 735 phosphorylation (pAbl T735 ) mediated by the type-IV secretion system (T4SS) effector D-glycero-β-D-manno-heptose-1,7-bisphosphate (βHBP) and protein kinase C (PKC) as a new c-Abl kinase. (
  • Importantly, in human patients suffering from Hp -mediated gastritis c-Abl expression and pAbl T735 phosphorylation were drastically enhanced as compared to type C gastritis patients or healthy individuals. (
  • Mediates phosphorylation of the BCR-ABL fusion protein. (
  • The expression of this protein is restricted to the fetal and adult hemo-lymphopoietic system, and it functions as a regulator of lymphocyte differentiation. (
  • Aim of the present study is to investigate the influence of hyperoxia on the protein expression using the differential analysis of protein expression in tissues (proteomics). (
  • expression of activating fusion proteins following translocations (e.g. (
  • A 22-nucleotide fragment of a transfer RNA regulates translation by binding to the mRNA of a ribosomal protein and increasing its expression, and downregulation of the fragment in patient-derived live. (
  • Bacterial expression plasmid containing His and MBP tags for 5 PRM motif repeats of Human Abl. (
  • When gene fusion happens in non-coding sequence region, it can lead to the misregulation of the expression of a gene now under the control of the cis-regulatory sequence of another gene. (
  • The expression levels of m-BCR/ABL in diagnostic samples differed up to 3 logs, being the lowest in patients expressing both variants of the fusion gene. (
  • In 38 samples from those patients, M-BCR/ABL expression was generally higher than m-BCR/ABL expression, being negative by m-BCR/ABL and positive by M-BCR/ABL in 13 samples. (
  • We show that all diagnostic samples should be screened for the simultaneous m- and M- BCR/ABL expression to avoid false-negativity when using m-BCR/ABL quantification only. (
  • however, in many cases, progression is accompanied by an increase in Bcr-Abl expression. (
  • We have determined that high levels of Bcr-Abl activate a signaling cascade involving the sequential activation of Ras, phosphatidylinositol-3 kinase, atypical protein kinase C, Raf-1, and mitogen-activated protein kinase kinase, leading to the ultimate expression of OPN. (
  • The data presented here define for the first time the ability of Bcr-Abl to stimulate the expression of OPN and also identify the signaling pathway involved. (
  • RNA expression has been studied on various array-based platforms, and protein expression has been analyzed by two-dimensional gel electrophoresis and by reverse-phase lysate array ( 7 ). (
  • This protein is essential, since the retroviral genome consists of RNA, while viral replication depends on expression from a reverse transcribed DNA copy that is integrated into the host genome as a cellular gene. (
  • Further functional analysis by minigene splicing assay showed that this variation, that is, c.801 + 1G>A, completely impairs normal splicing, then inactivating the expression of RhCE protein. (
  • Maybe patients with CML could be treated with a drug that blocks BCR-ABL, he hypothesized. (
  • Although CML and Ph + ALL are triggered by very similar BCR-ABL oncoproteins, durable responses of Ph + ALL patients to imatinib therapy are uncommon ( 11 ), and these patients, both pediatric and adult, receive other conventional combinational chemotherapy and/or bone marrow transplants to stem their disease. (
  • This contention is further supported by our pilot data on transplanted patients where BCR/ABL positivity preceding transplantation seems to be a better predictor of subsequent relapse than Ig/TCR approach. (
  • What the investigators learn could guide future research on treatments for patients with fusion protein-driven cancers," Dr. Witkin said. (
  • Patients are tested for BCR-ABL every 3 months according to established international guidelines. (
  • Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. (