Philadelphia Chromosome: 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).PhiladelphiaChromosomes, Human, 21-22 and Y: The short, acrocentric human chromosomes, called group G in the human chromosome classification. This group consists of chromosome pairs 21 and 22 and the Y chromosome.Leukemia, Myelogenous, Chronic, BCR-ABL Positive: 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.Fusion Proteins, bcr-abl: 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.Chromosomes: In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)Chromosome Mapping: Any method used for determining the location of and relative distances between genes on a chromosome.Benzamides: BENZOIC ACID amides.Blast Crisis: 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%.Chromosome Aberrations: Abnormal number or structure of chromosomes. Chromosome aberrations may result in CHROMOSOME DISORDERS.Chromosomes, Human, Pair 22: A specific pair of GROUP G CHROMOSOMES of the human chromosome classification.Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative: 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).Karyotyping: Mapping of the KARYOTYPE of a cell.Proto-Oncogene Proteins c-bcr: 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.PiperazinesPyrimidines: 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.Precursor Cell Lymphoblastic Leukemia-Lymphoma: 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.Chromosomes, Human, Pair 9: A specific pair of GROUP C CHROMSOMES of the human chromosome classification.Leukemia, Myeloid, Accelerated Phase: 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.Leukemia, Myeloid, Chronic-Phase: 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.Cytogenetics: A subdiscipline of genetics which deals with the cytological and molecular analysis of the CHROMOSOMES, and location of the GENES on chromosomes, and the movements of chromosomes during the CELL CYCLE.Translocation, Genetic: A type of chromosome aberration characterized by CHROMOSOME BREAKAGE and transfer of the broken-off portion to another location, often to a different chromosome.Leukemia, Myeloid: 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.Chromosomes, Human, 6-12 and X: The medium-sized, submetacentric human chromosomes, called group C in the human chromosome classification. This group consists of chromosome pairs 6, 7, 8, 9, 10, 11, and 12 and the X chromosome.Genes, abl: 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.Chromosome Disorders: Clinical conditions caused by an abnormal chromosome constitution in which there is extra or missing chromosome material (either a whole chromosome or a chromosome segment). (from Thompson et al., Genetics in Medicine, 5th ed, p429)Chromosome Banding: Staining of bands, or chromosome segments, allowing the precise identification of individual chromosomes or parts of chromosomes. Applications include the determination of chromosome rearrangements in malformation syndromes and cancer, the chemistry of chromosome segments, chromosome changes during evolution, and, in conjunction with cell hybridization studies, chromosome mapping.X Chromosome: The female sex chromosome, being the differential sex chromosome carried by half the male gametes and all female gametes in human and other male-heterogametic species.Sex Chromosomes: The homologous chromosomes that are dissimilar in the heterogametic sex. There are the X CHROMOSOME, the Y CHROMOSOME, and the W, Z chromosomes (in animals in which the female is the heterogametic sex (the silkworm moth Bombyx mori, for example)). In such cases the W chromosome is the female-determining and the male is ZZ. (From King & Stansfield, A Dictionary of Genetics, 4th ed)Leukemia, Neutrophilic, Chronic: 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).Chromosomes, Human, Pair 1: A specific pair of human chromosomes in group A (CHROMOSOMES, HUMAN, 1-3) of the human chromosome classification.Chromosomes, Human: Very long DNA molecules and associated proteins, HISTONES, and non-histone chromosomal proteins (CHROMOSOMAL PROTEINS, NON-HISTONE). Normally 46 chromosomes, including two sex chromosomes are found in the nucleus of human cells. They carry the hereditary information of the individual.Bone Marrow: 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.In Situ Hybridization, Fluorescence: 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.Chromosomes, Bacterial: Structures within the nucleus of bacterial cells consisting of or containing DNA, which carry genetic information essential to the cell.Chromosome Segregation: The orderly segregation of CHROMOSOMES during MEIOSIS or MITOSIS.Hobbies: Leisure activities engaged in for pleasure.Chromosomes, Human, Pair 7: A specific pair of GROUP C CHROMOSOMES of the human chromosome classification.Chromosomes, Human, Pair 11: A specific pair of GROUP C CHROMOSOMES of the human chromosome classification.Chromosome Deletion: Actual loss of portion of a chromosome.Gene Rearrangement: The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development.Remission Induction: Therapeutic act or process that initiates a response to a complete or partial remission level.Chromosomes, Human, Pair 17: A specific pair of GROUP E CHROMOSOMES of the human chromosome classification.Cytogenetic Analysis: Examination of CHROMOSOMES to diagnose, classify, screen for, or manage genetic diseases and abnormalities. Following preparation of the sample, KARYOTYPING is performed and/or the specific chromosomes are analyzed.Chromosomes, Human, Pair 6: A specific pair GROUP C CHROMSOMES of the human chromosome classification.Chromosomes, Human, Pair 21: A specific pair of GROUP G CHROMOSOMES of the human chromosome classification.Chromosomes, Plant: Complex nucleoprotein structures which contain the genomic DNA and are part of the CELL NUCLEUS of PLANTS.Protein-Tyrosine Kinases: Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.Chromosomes, Fungal: Structures within the nucleus of fungal cells consisting of or containing DNA, which carry genetic information essential to the cell.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Proto-Oncogene Proteins c-abl: 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.Metaphase: The phase of cell nucleus division following PROMETAPHASE, in which the CHROMOSOMES line up across the equatorial plane of the SPINDLE APPARATUS prior to separation.Oncogenes: 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.Leukemia, Lymphoid: Leukemia associated with HYPERPLASIA of the lymphoid tissues and increased numbers of circulating malignant LYMPHOCYTES and lymphoblasts.Chromosomes, Human, Pair 2: A specific pair of human chromosomes in group A (CHROMOSOMES, HUMAN, 1-3) of the human chromosome classification.Chromosomes, Human, Pair 16: A specific pair of GROUP E CHROMOSOMES of the human chromosome classification.Chromosome Pairing: The alignment of CHROMOSOMES at homologous sequences.Chromosomes, Mammalian: Complex nucleoprotein structures which contain the genomic DNA and are part of the CELL NUCLEUS of MAMMALS.Chromosomes, Human, Pair 13: A specific pair of GROUP D CHROMOSOMES of the human chromosome classification.Chromosomes, Human, Pair 4: A specific pair of GROUP B CHROMOSOMES of the human chromosome classification.Chromosomes, Human, Pair 10: A specific pair of GROUP C CHROMOSOMES of the human chromosome classification.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Neoplasm, Residual: Remnant of a tumor or cancer after primary, potentially curative therapy. (Dr. Daniel Masys, written communication)Chromosomes, Human, Y: The human male sex chromosome, being the differential sex chromosome carried by half the male gametes and none of the female gametes in humans.Chromosomes, Human, Pair 8: A specific pair of GROUP C CHROMOSOMES of the human chromosome classification.Chromosomes, Human, Pair 19: A specific pair of GROUP F CHROMOSOMES of the human chromosome classification.Molecular Sequence Data: 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.Chromosomes, Artificial, Bacterial: DNA constructs that are composed of, at least, a REPLICATION ORIGIN, for successful replication, propagation to and maintenance as an extra chromosome in bacteria. In addition, they can carry large amounts (about 200 kilobases) of other sequence for a variety of bioengineering purposes.Chromosomes, Human, X: The human female sex chromosome, being the differential sex chromosome carried by half the male gametes and all female gametes in humans.Chromosomes, Human, 1-3: The large, metacentric human chromosomes, called group A in the human chromosome classification. This group consists of chromosome pairs 1, 2, and 3.Chromosomes, Human, Pair 12: A specific pair of GROUP C CHROMOSOMES of the human chromosome classification.Chromosome Painting: A technique for visualizing CHROMOSOME ABERRATIONS using fluorescently labeled DNA probes which are hybridized to chromosomal DNA. Multiple fluorochromes may be attached to the probes. Upon hybridization, this produces a multicolored, or painted, effect with a unique color at each site of hybridization. This technique may also be used to identify cross-species homology by labeling probes from one species for hybridization with chromosomes from another species.Chromosomes, Human, Pair 5: One of the two pairs of human chromosomes in the group B class (CHROMOSOMES, HUMAN, 4-5).Blotting, Southern: 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.Chromosomes, Human, Pair 15: A specific pair of GROUP D CHROMOSOMES of the human chromosome classification.Precursor B-Cell Lymphoblastic Leukemia-Lymphoma: A leukemia/lymphoma found predominately in children and adolescents and characterized by a high number of lymphoblasts and solid tumor lesions. Frequent sites involve LYMPH NODES, skin, and bones. It most commonly presents as leukemia.Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells. In addition to antiviral activity, it activates NATURAL KILLER CELLS and B-LYMPHOCYTES, and down-regulates VASCULAR ENDOTHELIAL GROWTH FACTOR expression through PI-3 KINASE and MAPK KINASES signaling pathways.Chromosomes, Human, Pair 14: A specific pair of GROUP D CHROMOSOMES of the human chromosome classification.Chromosomes, Human, Pair 18: A specific pair of GROUP E CHROMOSOMES of the human chromosome classification.History, 21st Century: Time period from 2001 through 2100 of the common era.Chromosomes, Human, 16-18: The short, submetacentric human chromosomes, called group E in the human chromosome classification. This group consists of chromosome pairs 16, 17, and 18.Chromosomes, Human, Pair 20: A specific pair of GROUP F CHROMOSOMES of the human chromosome classification.Chromosomes, Artificial, Yeast: Chromosomes in which fragments of exogenous DNA ranging in length up to several hundred kilobase pairs have been cloned into yeast through ligation to vector sequences. These artificial chromosomes are used extensively in molecular biology for the construction of comprehensive genomic libraries of higher organisms.Prognosis: A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations.Chromosomes, Human, 13-15: The medium-sized, acrocentric human chromosomes, called group D in the human chromosome classification. This group consists of chromosome pairs 13, 14, and 15.Protein Kinase Inhibitors: Agents that inhibit PROTEIN KINASES.Genetic Linkage: The co-inheritance of two or more non-allelic GENES due to their being located more or less closely on the same CHROMOSOME.Polymerase Chain Reaction: 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.ThiazolesChromosome Breakage: A type of chromosomal aberration involving DNA BREAKS. Chromosome breakage can result in CHROMOSOMAL TRANSLOCATION; CHROMOSOME INVERSION; or SEQUENCE DELETION.Bone Marrow Transplantation: The transference of BONE MARROW from one human or animal to another for a variety of purposes including HEMATOPOIETIC STEM CELL TRANSPLANTATION or MESENCHYMAL STEM CELL TRANSPLANTATION.Ring Chromosomes: Aberrant chromosomes with no ends, i.e., circular.Proto-Oncogenes: 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.Chromosome Inversion: An aberration in which a chromosomal segment is deleted and reinserted in the same place but turned 180 degrees from its original orientation, so that the gene sequence for the segment is reversed with respect to that of the rest of the chromosome.Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event.Chromosome Positioning: The mechanisms of eukaryotic CELLS that place or keep the CHROMOSOMES in a particular SUBNUCLEAR SPACE.Drug Resistance, Neoplasm: Resistance or diminished response of a neoplasm to an antineoplastic agent in humans, animals, or cell or tissue cultures.Chromosomes, Human, 4-5: The large, submetacentric human chromosomes, called group B in the human chromosome classification. This group consists of chromosome pairs 4 and 5.DNA, Neoplasm: DNA present in neoplastic tissue.Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive.Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, and practicability of these interventions in individual cases or series.X Chromosome Inactivation: A dosage compensation process occurring at an early embryonic stage in mammalian development whereby, at random, one X CHROMOSOME of the pair is repressed in the somatic cells of females.Proto-Oncogene Proteins: 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.Clone Cells: A group of genetically identical cells all descended from a single common ancestral cell by mitosis in eukaryotes or by binary fission in prokaryotes. Clone cells also include populations of recombinant DNA molecules all carrying the same inserted sequence. (From King & Stansfield, Dictionary of Genetics, 4th ed)Cell Line: Established cell cultures that have the potential to propagate indefinitely.Neoplastic Stem Cells: Highly proliferative, self-renewing, and colony-forming stem cells which give rise to NEOPLASMS.PennsylvaniaCentromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division.Tumor Cells, Cultured: 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.Vincristine: An antitumor alkaloid isolated from VINCA ROSEA. (Merck, 11th ed.)Cell Transformation, Neoplastic: 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.RNA, Messenger: 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.Chromosomes, Insect: Structures within the CELL NUCLEUS of insect cells containing DNA.Mutation: 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.Meiosis: A type of CELL NUCLEUS division, occurring during maturation of the GERM CELLS. Two successive cell nucleus divisions following a single chromosome duplication (S PHASE) result in daughter cells with half the number of CHROMOSOMES as the parent cells.Hybrid Cells: Any cell, other than a ZYGOTE, that contains elements (such as NUCLEI and CYTOPLASM) from two or more different cells, usually produced by artificial CELL FUSION.Disease-Free Survival: Period after successful treatment in which there is no appearance of the symptoms or effects of the disease.Chromosome Structures: Structures which are contained in or part of CHROMOSOMES.Chromosomes, Human, 19-20: The short, metacentric human chromosomes, called group F in the human chromosome classification. This group consists of chromosome pairs 19 and 20.Antineoplastic Combined Chemotherapy Protocols: The use of two or more chemicals simultaneously or sequentially in the drug therapy of neoplasms. The drugs need not be in the same dosage form.Survival Analysis: A class of statistical procedures for estimating the survival function (function of time, starting with a population 100% well at a given time and providing the percentage of the population still well at later times). The survival analysis is then used for making inferences about the effects of treatments, prognostic factors, exposures, and other covariates on the function.Transplantation, Homologous: Transplantation between individuals of the same species. Usually refers to genetically disparate individuals in contradistinction to isogeneic transplantation for genetically identical individuals.Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of CHROMOSOMES, chromosome pairs, or chromosome fragments. In a normally diploid cell (DIPLOIDY) the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is MONOSOMY (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is TRISOMY (symbol: 2N+1).Time Factors: Elements of limited time intervals, contributing to particular results or situations.Mitosis: A type of CELL NUCLEUS division by means of which the two daughter nuclei normally receive identical complements of the number of CHROMOSOMES of the somatic cells of the species.Leukemia, Myeloid, Acute: Clonal expansion of myeloid blasts in bone marrow, blood, and other tissue. Myeloid leukemias develop from changes in cells that normally produce NEUTROPHILS; BASOPHILS; EOSINOPHILS; and MONOCYTES.Hematopoietic Stem Cell Transplantation: Transfer of HEMATOPOIETIC STEM CELLS from BONE MARROW or BLOOD between individuals within the same species (TRANSPLANTATION, HOMOLOGOUS) or transfer within the same individual (TRANSPLANTATION, AUTOLOGOUS). Hematopoietic stem cell transplantation has been used as an alternative to BONE MARROW TRANSPLANTATION in the treatment of a variety of neoplasms.Pedigree: The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition.Bone Marrow Cells: Cells contained in the bone marrow including fat cells (see ADIPOCYTES); STROMAL CELLS; MEGAKARYOCYTES; and the immediate precursors of most blood cells.Phenotype: The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.Recombination, Genetic: Production of new arrangements of DNA by various mechanisms such as assortment and segregation, CROSSING OVER; GENE CONVERSION; GENETIC TRANSFORMATION; GENETIC CONJUGATION; GENETIC TRANSDUCTION; or mixed infection of viruses.Lod Score: The total relative probability, expressed on a logarithmic scale, that a linkage relationship exists among selected loci. Lod is an acronym for "logarithmic odds."Crosses, Genetic: Deliberate breeding of two different individuals that results in offspring that carry part of the genetic material of each parent. The parent organisms must be genetically compatible and may be from different varieties or closely related species.Microsatellite Repeats: A variety of simple repeat sequences that are distributed throughout the GENOME. They are characterized by a short repeat unit of 2-8 basepairs that is repeated up to 100 times. They are also known as short tandem repeats (STRs).Nucleic Acid Hybridization: Widely used technique which exploits the ability of complementary sequences in single-stranded DNAs or RNAs to pair with each other to form a double helix. Hybridization can take place between two complimentary DNA sequences, between a single-stranded DNA and a complementary RNA, or between two RNA sequences. The technique is used to detect and isolate specific sequences, measure homology, or define other characteristics of one or both strands. (Kendrew, Encyclopedia of Molecular Biology, 1994, p503)Follow-Up Studies: Studies in which individuals or populations are followed to assess the outcome of exposures, procedures, or effects of a characteristic, e.g., occurrence of disease.Morale: The prevailing temper or spirit of an individual or group in relation to the tasks or functions which are expected.Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods.DNA Probes: Species- or subspecies-specific DNA (including COMPLEMENTARY DNA; conserved genes, whole chromosomes, or whole genomes) used in hybridization studies in order to identify microorganisms, to measure DNA-DNA homologies, to group subspecies, etc. The DNA probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the DNA probe include the radioisotope labels 32P and 125I and the chemical label biotin. The use of DNA probes provides a specific, sensitive, rapid, and inexpensive replacement for cell culture techniques for diagnosing infections.Alleles: Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product.DNA: 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).Cloning, Molecular: 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.Isochromosomes: Metacentric chromosomes produced during MEIOSIS or MITOSIS when the CENTROMERE splits transversely instead of longitudinally. The chromosomes produced by this abnormal division are one chromosome having the two long arms of the original chromosome, but no short arms, and the other chromosome consisting of the two short arms and no long arms. Each of these isochromosomes constitutes a simultaneous duplication and deletion.Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell.Amino Acid Sequence: 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.Nondisjunction, Genetic: The failure of homologous CHROMOSOMES or CHROMATIDS to segregate during MITOSIS or MEIOSIS with the result that one daughter cell has both of a pair of parental chromosomes or chromatids and the other has none.Genotype: The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS.Genes: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.Chromosomes, Artificial, Human: DNA constructs that are composed of, at least, all elements, such as a REPLICATION ORIGIN; TELOMERE; and CENTROMERE, required for successful replication, propagation to and maintainance in progeny human cells. In addition, they are constructed to carry other sequences for analysis or gene transfer.Kinetochores: Large multiprotein complexes that bind the centromeres of the chromosomes to the microtubules of the mitotic spindle during metaphase in the cell cycle.Telomere: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs.Heterozygote: An individual having different alleles at one or more loci regarding a specific character.Chromosome Walking: A technique with which an unknown region of a chromosome can be explored. It is generally used to isolate a locus of interest for which no probe is available but that is known to be linked to a gene which has been identified and cloned. A fragment containing a known gene is selected and used as a probe to identify other overlapping fragments which contain the same gene. The nucleotide sequences of these fragments can then be characterized. This process continues for the length of the chromosome.Chromosomal Proteins, Non-Histone: Nucleoproteins, which in contrast to HISTONES, are acid insoluble. They are involved in chromosomal functions; e.g. they bind selectively to DNA, stimulate transcription resulting in tissue-specific RNA synthesis and undergo specific changes in response to various hormones or phytomitogens.Chromosomal Instability: An increased tendency to acquire CHROMOSOME ABERRATIONS when various processes involved in chromosome replication, repair, or segregation are dysfunctional.Spindle Apparatus: A microtubule structure that forms during CELL DIVISION. It consists of two SPINDLE POLES, and sets of MICROTUBULES that may include the astral microtubules, the polar microtubules, and the kinetochore microtubules.Models, Genetic: Theoretical representations that simulate the behavior or activity of genetic processes or phenomena. They include the use of mathematical equations, computers, and other electronic equipment.Sequence Analysis, DNA: A multistage process that includes cloning, physical mapping, subcloning, determination of the DNA SEQUENCE, and information analysis.Chromosome Fragility: Susceptibility of chromosomes to breakage leading to translocation; CHROMOSOME INVERSION; SEQUENCE DELETION; or other CHROMOSOME BREAKAGE related aberrations.Polymorphism, Restriction Fragment Length: Variation occurring within a species in the presence or length of DNA fragment generated by a specific endonuclease at a specific site in the genome. Such variations are generated by mutations that create or abolish recognition sites for these enzymes or change the length of the fragment.Quantitative Trait Loci: Genetic loci associated with a QUANTITATIVE TRAIT.Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the MAJOR HISTOCOMPATIBILITY COMPLEX.Chromosome Duplication: An aberration in which an extra chromosome or a chromosomal segment is made.DNA, Satellite: Highly repetitive DNA sequences found in HETEROCHROMATIN, mainly near centromeres. They are composed of simple sequences (very short) (see MINISATELLITE REPEATS) repeated in tandem many times to form large blocks of sequence. Additionally, following the accumulation of mutations, these blocks of repeats have been repeated in tandem themselves. The degree of repetition is on the order of 1000 to 10 million at each locus. Loci are few, usually one or two per chromosome. They were called satellites since in density gradients, they often sediment as distinct, satellite bands separate from the bulk of genomic DNA owing to a distinct BASE COMPOSITION.Drosophila melanogaster: A species of fruit fly much used in genetics because of the large size of its chromosomes.Myeloproliferative Disorders: 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.Repetitive Sequences, Nucleic Acid: Sequences of DNA or RNA that occur in multiple copies. There are several types: INTERSPERSED REPETITIVE SEQUENCES are copies of transposable elements (DNA TRANSPOSABLE ELEMENTS or RETROELEMENTS) dispersed throughout the genome. TERMINAL REPEAT SEQUENCES flank both ends of another sequence, for example, the long terminal repeats (LTRs) on RETROVIRUSES. Variations may be direct repeats, those occurring in the same direction, or inverted repeats, those opposite to each other in direction. TANDEM REPEAT SEQUENCES are copies which lie adjacent to each other, direct or inverted (INVERTED REPEAT SEQUENCES).Diploidy: The chromosomal constitution of cells, in which each type of CHROMOSOME is represented twice. Symbol: 2N or 2X.Evolution, Molecular: The process of cumulative change at the level of DNA; RNA; and PROTEINS, over successive generations.Chromatids: Either of the two longitudinally adjacent threads formed when a eukaryotic chromosome replicates prior to mitosis. The chromatids are held together at the centromere. Sister chromatids are derived from the same chromosome. (Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)Gene Amplification: A selective increase in the number of copies of a gene coding for a specific protein without a proportional increase in other genes. It occurs naturally via the excision of a copy of the repeating sequence from the chromosome and its extrachromosomal replication in a plasmid, or via the production of an RNA transcript of the entire repeating sequence of ribosomal RNA followed by the reverse transcription of the molecule to produce an additional copy of the original DNA sequence. Laboratory techniques have been introduced for inducing disproportional replication by unequal crossing over, uptake of DNA from lysed cells, or generation of extrachromosomal sequences from rolling circle replication.Building Codes: Standards or regulations for construction which are designed to ensure safety against electrical hazards, fires, etc.Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single ZYGOTE, as opposed to CHIMERISM in which the different cell populations are derived from more than one zygote.Harringtonines: Tetracyclic spiro-BENZAZEPINES isolated from the seeds of CEPHALOTAXUS. They are esters of the alkaloid cephalotaxine and may be effective as antineoplastic agents.Exons: The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.
Philadelphia Badlands: The Philadelphia Badlands is a section of North Philadelphia, Pennsylvania, United States that is known for an abundance of open-air recreational drug markets and drug-related violence.Volk, Steve.Premature chromosome condensation: Premature chromosome condensation (PCC) occurs in eukaryotic organisms when mitotic cells fuse with interphase cells. Chromatin, a substance that contains genetic material such as DNA, is normally found in a loose bundle inside a cell's nucleus.Chromosome regionsImatinibGenetic imbalance: Genetic imbalance is to describe situation when the genome of a cell or organism has more copies of some genes than other genes due to chromosomal rearrangements or aneuploidy.BCR (gene): The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a protein that in humans is encoded by the BCR gene. BCR is one of the two genes in the BCR-ABL complex, which is associated with the Philadelphia chromosome.PiperazinePyrazolopyrimidineOncogene: An oncogene is a gene that has the potential to cause cancer.Wilbur, Beth, editor.Myeloid leukemiaSmith–Fineman–Myers syndrome: Smith–Fineman–Myers syndrome (SFMS1), also called X-linked mental retardation-hypotonic facies syndrome 1 (MRXHF1), Carpenter–Waziri syndrome, Chudley–Lowry syndrome, SFMS, Holmes–Gang syndrome and Juberg–Marsidi syndrome (JMS), is a rare X-linked recessive congenital disorder that causes birth defects. This syndrome was named after 3 men, Richard D.Chronic neutrophilic leukemiaBone marrow suppression: Bone marrow suppression or myelotoxicity (adjective myelotoxic) or myelosuppression is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (thrombocytes). Bone marrow suppression is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine.Circular bacterial chromosome: A circular bacterial chromosome is a bacterial chromosome in the form of a molecule of circular DNA. Unlike the linear DNA of most eukaryotes, typical bacterial chromosomes are circular.Immortal DNA strand hypothesis: The immortal DNA strand hypothesis was proposed in 1975 by John Cairns as a mechanism for adult stem cells to minimize mutations in their genomes.Cairns, J.Gladys Lounsbury Hobby: Gladys Lounsbury Hobby (November 19, 1910 – July 4, 1993), born in New York City, was an American microbiologist who helped to move penicillin from a laboratory discovery to mass production during World War II.Chromothripsis: Chromothripsis is the phenomenon by which up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomes, and is known to be involved in both cancer and congenital diseases. It occurs through one massive genomic rearrangement during a single catastrophic event in the cell's history.Transient neonatal diabetes mellitusTyrosine-kinase inhibitor: A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades.Antileukemic drug: Antileukemic drugs, anticancer drugs that are used to treat one or more types of leukemia, include:Metaphase: Metaphase (from the Greek μετά, "adjacent" and φάσις, "stage") is a stage of mitosis in the eukaryotic cell cycle in which chromosomes are at their second-most condensed and coiled stage (they are at their most condensed in anaphase. These chromosomes, carrying genetic information, align in the equator of the cell before being separated into each of the two daughter cells.Symmetry element: A symmetry element is a point of reference about which symmetry operations can take place. In particular, symmetry elements can be centers of inversion, axes of rotation and mirror planes.Coles PhillipsGenetic linkage: Genetic linkage is the tendency of alleles that are located close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Genes whose loci are nearer to each other are less likely to be separated onto different chromatids during chromosomal crossover, and are therefore said to be genetically linked.Thermal cyclerThiazolineBone Marrow Transplantation (journal): Bone Marrow Transplantation is a peer-reviewed medical journal covering transplantation of bone marrow in humans. It is published monthly by the Nature Publishing Group.Ring chromosome: A ring chromosome is a chromosome whose arms have fused together to form a ring. Ring chromosomes were first discovered by Lilian Vaughan Morgan in 1926.John Payne ToddMyeloid: The term myeloid (myelogenous) is an adjective that can refer to a progenitor cell for granulocytes, monocytes, erythrocytes, or platelets. Myeloid can be distinguished from the lymphoid progenitor cells that give rise to B cells and T cells.
(1/390) Autografting with philadelphia chromosome-negative mobilized hematopoietic progenitor cells in chronic myelogenous leukemia.
Intensive chemotherapy given in early chronic phase of chronic myelogenous leukemia (CML) has resulted in high numbers of circulating Philadelphia (Ph) chromosome-negative hematopoietic progenitor cells (HPC). We have autografted 30 consecutive patients with CML in chronic phase with HPC collected in this way to facilitate restoration of Ph-negative hematopoiesis in bone marrow after high-dose therapy. Hematopoietic recovery to greater than 0.5 x10(9)/L neutrophils and to greater than 25 x 10(9)/L platelets occurred in all patients, a median of 13 (range, 9 to 32) days and 16 (range, 6 to 106) days postautograft, respectively. Regenerating marrow cells were Ph-negative in 16 (53%) patients and greater than 66% Ph-negative in 10 (33%) patients. Twenty-eight patients are alive 6 to 76 months (median, 24 months) after autografting. Three patients have developed blast crisis from which 2 have died. Eight patients are in complete cytogenetic remission at a median of 20 (range, 6 to 44) months with a median ratio BCR-ABL/ABL of 0.002 (range, <0.001 to 0.01). Eight patients are in major cytogenetic remission at a median of 22 (range, 6 to 48) months. No patient died as a consequence of the treatment. All patients had some degree of stomatitis that was severe in 15 (50%) patients. Gastrointestinal and hepatic toxicities were observed in about one fourth of patients. Thus, autografting with Ph-negative mobilized HPC can result in prolonged restoration of Ph-negative hematopoiesis for some patients with CML; moreover, most autograft recipients report normal or near normal activity levels, suggesting that this procedure need not to be associated either with prolonged convalescence or with chronic debility. (+info)
(2/390) Extremely high and specific activity of DNA enzymes in cells with a Philadelphia chromosome.
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)
(3/390) Selective induction of apoptosis in Philadelphia chromosome-positive chronic myelogenous leukemia cells by an inhibitor of BCR - ABL tyrosine kinase, CGP 57148.
The BCR - ABL tyrosine kinase has been implicated as the cause of Philadelphia chromosome (Ph1)-positive leukemias. We report herein that CGP 57148, a selective inhibitor of the ABL tyrosine kinase, caused apoptosis specifically in bcr - abl-positive chronic myelogenous leukemia (CML) cells, K562 and KYO-1. Upon treatment with CGP 57148, CRKL, a specific substrate for BCR - ABL that propagates signals via phosphatidylinositol-3' kinase (PI3K), was dephosphorylated, indicating inhibition of BCR - ABL tyrosine kinase at the cellular level. Likewise, MAPK/ERK, a downstream mediator of Ras, was also dephosphorylated. Caspase activation and cleavage of retinoblastoma protein (pRB) accompanied the development of CGP 57148-induced apoptosis. Inhibition of caspase suppressed apoptosis and the cleavage of pRB, and in turn arrested cells in the G1 phase. These results indicate that CGP 57148 shows apoptogenic and anti-proliferative effects on bcr - abl-positive cells by blocking BCR - ABL-initiated signaling pathways. (+info)
(4/390) Relapse in chronic myeloid leukemia after bone marrow transplantation: biomathematical modeling as a new approach to understanding pathogenesis.
A biomathematical model was developed to simulate relapse development in patients with chronic myeloid leukemia (CML) following bone marrow transplantation (BMT). The purpose of this study was to better understand the pathophysiology of the time evolution of CML relapse and to provide means whereby the outcomes of patients with CML relapse can be projected and treatment modified accordingly. The model consists of three parallel series of catenated compartments representing granulopoiesis in normal (donor) cells from the marrow, in CML cells from the marrow, and in CML cells from extramedullary sites. It was assumed that CML stem cells were resistant to feedback control and that CML-derived neutrophils, as well as normal neutrophils, exercised feedback regulation of normal stem cells. The known longer generation times for CML neutrophil precursors compared with normal neutrophil precursors were used, and it was assumed that 10(7) pluripotential stem cells were infused with BMT. The model was evaluated for its ability to simulate the reappearance of CML (Philadelphia chromosome positive) metaphases in the marrow and the recovery pattern in the blood neutrophil count in six patients who had relapsed following BMT (allogeneic in three patients, allogeneic with T-cell depletion in two patients, and syngeneic in one patient). The variables tested included the site of origin of the CML stem cells responsible for relapse (marrow alone versus marrow and extramedullary sites), the minimum number of CML stem cells responsible for relapse, and the time delay between BMT and the onset of relapse. Model profiles based on the observed values were obtained in each case. The simulations pointed to the fact that relapse began from a small number of CML cells in medullary and extramedullary sites. The time delay between BMT and the onset of relapse varied from 15 to 240 days. We suggest that this biomathematical model should be further investigated as a possible means of predicting outcome and guiding the treatment for patients with CML relapsing after BMT. (+info)
(5/390) The prognostic significance of p16INK4a/p14ARF and p15INK4b deletions in adult acute lymphoblastic leukemia.
Cytogenetic/molecular abnormalities significantly influence the prognosis of patients with acute leukemia. Recently, two genes, p16INK4a and p15INK4b, encoding two cyclin-dependent kinase inhibitor proteins of the INK4 family of Mr 15,000 and 16,000, respectively, have been localized to 9p21. Remarkably, the p16INK4a locus has been found to encode a second protein, p14ARF, known as p19ARF in mice, with a distinct reading frame. Like p16INK4a, p14ARF is involved in cell cycle regulation, blocking cells at the G1 restriction point through the activity of MDM-2 and p53. We studied bone marrow samples of 42 newly diagnosed and untreated patients with acute lymphoblastic leukemia for the incidence of deletions of p16INK4a/p14ARF and p15INK4b using Southern blot analysis and determined the clinical outcome with regard to complete remission (CR) duration, event-free survival, and overall survival. We found deletions of p16INK4a/p14ARF in 17 of 42 patients (40%), with homozygous deletions in 11 of 42 patients (26%) and hemizygous deletions in 6 of 42 patients (14%). The gene for p15INK4b was codeleted in most, but not all, cases and was never deleted without deletion of p16INK4a/ p14ARF. No correlation was observed between molecular studies and karyotype abnormalities as determined by conventional cytogenetics. Furthermore, no difference was found in the CR rate, CR duration, event-free survival, and overall survival in patients with homozygous gene deletions compared to patients with no deletions or loss of only one allele. (+info)
(6/390) BCR/ABL mRNA and the P210(BCR/ABL) protein are downmodulated by interferon-alpha in chronic myeloid leukemia patients.
The BCR/ABL hybrid gene plays a central role in the pathogenesis of the chronic phase of chronic myeloid leukemia (CML). We used a very sensitive quantitative reverse transcriptase-polymerase chain reaction to investigate the levels of hybrid BCR/ABL mRNA in bone marrow cells of 20 patients with Philadelphia positive (Ph(+)) CML treated with interferon-alpha (IFN-alpha) as a single agent. Bone marrow samples were collected at diagnosis and at hematologic remission induced by IFN-alpha, or by hydroxyurea in case of resistance to IFN-alpha. The mean levels of BCR/ABL transcripts in bone marrow mononuclear cells of patients who showed a complete hematologic response to IFN-alpha were significantly reduced with respect to those at diagnosis (48 x 10(3) v 168 x 10(3); P <.001), whereas no difference was detected between the values at diagnosis and at hematologic remission in patients resistant to IFN-alpha. In cell culture experiments, IFN-alpha priming significantly reduced the levels of BCR/ABL hybrid transcripts in a dose-dependent manner in Ph+ bone marrow precursors obtained at diagnosis from patients who subsequently responded to IFN-alpha treatment (P < .005). No downmodulation was observed in bone marrow precursors from patients who subsequently proved to be IFN-resistant. These results indicate that downmodulation of BCR/ABL gene expression could be one of the mechanisms involved in the response of CML patients to IFN-alpha treatment. (+info)
(7/390) ABL1 methylation is a distinct molecular event associated with clonal evolution of chronic myeloid leukemia.
Methylation of the proximal promoter of the ABL1 oncogene is a common epigenetic alteration associated with clinical progression of chronic myeloid leukemia (CML). In this study we queried whether both the Ph'-associated and normal ABL1 alleles undergo methylation; what may be the proportion of hematopoietic progenitors bearing methylated ABL1 promoters in chronic versus acute phase disease; whether methylation affects the promoter uniformly or in patches with discrete clinical relevance; and, finally, whether methylation of ABL1 reflects a generalized process or is gene-specific. To address these issues, we adapted the techniques of methylation-specific PCR and bisulfite-sequencing to study the regulatory regions of ABL1 and other genes with a role in DNA repair or genotoxic stress response. In cell lines established from CML blast crisis, which only carry a single ABL1 allele nested within the BCR-ABL fusion gene, ABL1 promoters were universally methylated. By contrast, in clinical samples from patients at advanced stages of disease, both methylated and unmethylated promoter alleles were detectable. To distinguish between allele-specific methylation and a mixed cell population pattern, we studied the methylation status of ABL1 in colonies derived from single hematopoietic progenitors. Our results showed that both methylated and unmethylated promoter alleles coexisted in the same colony. Furthermore, ABL1 methylation was noted in the vast majority of colonies from blast crisis, but not chronic-phase CML. Both cell lines and clinical samples from acute-phase CML showed nearly uniform hypermethylation along the promoter region. Finally, we showed that ABL1 methylation does not reflect a generalized process and may be unique among DNA repair/genotoxic stress response genes. Our data suggest that specific methylation of the Ph'-associated ABL1 allele accompanies clonal evolution in CML. (+info)
(8/390) Analysis of Philadelphia chromosome-negative BCR-ABL-positive chronic myelogenous leukemia by hypermetaphase fluorescence in situ hybridization.
BACKGROUND: In 5%-10% of patients with of chronic myelogenous leukemia (CML), the Philadelphia chromosome (Ph) is not identified, despite the presence of the associated BCR-ABL molecular abnormality (Ph-negative, BCR-ABL-positive CML) because of sub-microscopic rearrangements. PATIENTS AND METHODS: Six patients with Ph-negative, BCR-ABL-positive CML were investigated. The Ph chromosome detection via fluorescence in situ hybridization after 24-hour mitotic arrest of bone marrow cultures resulting in several hundreds of metaphases (hypermetaphase FISH or HMF) was useful in explaining the nature of the six cases. RESULTS: Four patients had a low frequency of Ph-positive cells by HMF (5.7%, 4.8%, 3.9%, 0.2%), i.e., a typical Ph translocation. However, two cases involved a 9q34 inserted into chromosome 22q11 (74.2% and 92%), without a deletion from chromosome 22 and reciprocal translocation onto 9, i.e., not a typical Ph translocation. The pattern of UBCR gene rearrangement was characterized by the same genomic recombination of 5-BCR and c-ABL, both in the four cases of typical translocation (9;22) and in the two cases of insertion of 9q34 into chromosome 22q11. CONCLUSIONS: The HMF identified two different bases for Ph-negative, BCR-ABL-positive cells in CML-presence of low frequency of cells with typical Ph translocations or presence of cells with ABL insertions into the BCR gene on chromosome 22. (+info)