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%.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.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.Benzamides: BENZOIC ACID amides.Crisis Intervention: Brief therapeutic approach which is ameliorative rather than curative of acute psychiatric emergencies. Used in contexts such as emergency rooms of psychiatric or general hospitals, or in the home or place of crisis occurrence, this treatment approach focuses on interpersonal and intrapsychic factors and environmental modification. (APA Thesaurus of Psychological Index Terms, 7th ed)Blast Injuries: Injuries resulting when a person is struck by particles impelled with violent force from an explosion. Blast causes pulmonary concussion and hemorrhage, laceration of other thoracic and abdominal viscera, ruptured ear drums, and minor effects in the central nervous system. (From Dorland, 27th ed)PiperazinesLeukemia, 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.Pyrimidines: 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.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).Chromosomes, 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.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.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.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.Granulocyte-Macrophage Progenitor Cells: The parent cells that give rise to both cells of the GRANULOCYTE lineage and cells of the monocyte/macrophage lineage.Gene Expression Regulation, Leukemic: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in leukemia.Leukemia, Lymphoid: Leukemia associated with HYPERPLASIA of the lymphoid tissues and increased numbers of circulating malignant LYMPHOCYTES and lymphoblasts.Thyroid Crisis: A dangerous life-threatening hypermetabolic condition characterized by high FEVER and dysfunction of the cardiovascular, the nervous, and the gastrointestinal systems.K562 Cells: An ERYTHROLEUKEMIA cell line derived from a CHRONIC MYELOID LEUKEMIA patient in BLAST CRISIS.Leukemia: 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)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.Anemia, Refractory, with Excess of Blasts: Chronic refractory anemia with granulocytopenia, and/or thrombocytopenia. Myeloblasts and progranulocytes constitute 5 to 40 percent of the nucleated marrow cells.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.Karyotyping: Mapping of the KARYOTYPE of a cell.Chromosomes, Human, Pair 22: A specific pair of GROUP G CHROMOSOMES of the human chromosome classification.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.Neoplastic Stem Cells: Highly proliferative, self-renewing, and colony-forming stem cells which give rise to NEOPLASMS.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Blood Cell Count: The number of LEUKOCYTES and ERYTHROCYTES per unit volume in a sample of venous BLOOD. A complete blood count (CBC) also includes measurement of the HEMOGLOBIN; HEMATOCRIT; and ERYTHROCYTE INDICES.Chromosomes, Human, Pair 9: A specific pair of GROUP C CHROMSOMES of the human chromosome classification.Acute Disease: Disease having a short and relatively severe course.Drug Resistance, Neoplasm: Resistance or diminished response of a neoplasm to an antineoplastic agent in humans, animals, or cell or tissue cultures.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.Cytarabine: A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472)Economic Recession: Significant decline in economic activity spread across the economy, lasting more than a few months, normally visible in real gross domestic product, real income, employment, industrial production, and wholesale-retail sales. (National Bureau of Economic Research, Inc, www.nber.org/cycles.html, accessed 4/23/2009)Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups according to the staining properties of the granules: neutrophilic, eosinophilic, and basophilic. Mature granulocytes are the NEUTROPHILS; EOSINOPHILS; and BASOPHILS.Chromosome Aberrations: Abnormal number or structure of chromosomes. Chromosome aberrations may result in CHROMOSOME DISORDERS.Gene Rearrangement: The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development.Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive.Anemia, Sickle Cell: A disease characterized by chronic hemolytic anemia, episodic painful crises, and pathologic involvement of many organs. It is the clinical expression of homozygosity for hemoglobin S.Remission Induction: Therapeutic act or process that initiates a response to a complete or partial remission level.Myelodysplastic Syndromes: Clonal hematopoietic stem cell disorders characterized by dysplasia in one or more hematopoietic cell lineages. They predominantly affect patients over 60, are considered preleukemic conditions, and have high probability of transformation into ACUTE MYELOID LEUKEMIA.Protein-Tyrosine Kinases: Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.Antigens, CD34: 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.RNA, Neoplasm: RNA present in neoplastic tissue.Nucleotidases: A class of enzymes that catalyze the conversion of a nucleotide and water to a nucleoside and orthophosphate. EC 3.1.3.-.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.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.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.Antigens, Surface: Antigens on surfaces of cells, including infectious or foreign cells or viruses. They are usually protein-containing groups on cell membranes or walls and may be isolated.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.Myeloid Progenitor Cells: Stem cells derived from HEMATOPOIETIC STEM CELLS. Derived from these myeloid progenitor cells are the MEGAKARYOCYTES; ERYTHROID CELLS; MYELOID CELLS; and some DENDRITIC CELLS.Nucleoside Deaminases: Catalyze the hydrolysis of nucleosides with the elimination of ammonia.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.5'-Nucleotidase: A glycoprotein enzyme present in various organs and in many cells. The enzyme catalyzes the hydrolysis of a 5'-ribonucleotide to a ribonucleoside and orthophosphate in the presence of water. It is cation-dependent and exists in a membrane-bound and soluble form. EC 188.8.131.52.Antigens, Neoplasm: Proteins, glycoprotein, or lipoprotein moieties on surfaces of tumor cells that are usually identified by monoclonal antibodies. Many of these are of either embryonic or viral origin.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.DNA, Neoplasm: DNA present in neoplastic tissue.PhenanthrenesBlotting, 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 3: A specific pair of human chromosomes in group A (CHROMOSOMES, HUMAN, 1-3) of the human chromosome classification.Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis.Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.Tumor Stem Cell Assay: 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.Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each), or NATURAL KILLER CELLS.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.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.Protein Kinase Inhibitors: Agents that inhibit PROTEIN KINASES.Immunophenotyping: Process of classifying cells of the immune system based on structural and functional differences. The process is commonly used to analyze and sort T-lymphocytes into subsets based on CD antigens by the technique of flow cytometry.Adenosine Deaminase: An enzyme that catalyzes the hydrolysis of ADENOSINE to INOSINE with the elimination of AMMONIA.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.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.Oryza sativa: Annual cereal grass of the family POACEAE and its edible starchy grain, rice, which is the staple food of roughly one-half of the world's population.B-Lymphocytes: 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.ExplosionsApoptosis: 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.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Transplantation, Homologous: Transplantation between individuals of the same species. Usually refers to genetically disparate individuals in contradistinction to isogeneic transplantation for genetically identical individuals.Recurrence: The return of a sign, symptom, or disease after a remission.Manuals as Topic: Books designed to give factual information or instructions.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.Thiazoles
Myeloid leukemiaImatinibOntario Correctional ServicesBlast injury: A blast injury is a complex type of physical trauma resulting from direct or indirect exposure to an explosion. Blast injuries occur with the detonation of high-order explosives as well as the deflagration of low order explosives.PiperazinePyrazolopyrimidineMinimally differentiated acute myeloblastic leukemiaChildhood leukemia: Childhood leukemia is a type of leukemia, usually acute lymphocytic leukemia (ALL), and a type of childhood cancer. The cure rate of childhood leukemia is generally higher than adult leukemia, approaching 90%, although some side effects of treatment last into adulthood.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.Bone 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.Stem cell theory of aging: The stem cell theory of aging is a new theory which was formulated by several scientists and which postulates that the aging process is the result of the inability of various types of stem cells to continue to replenish the tissues of an organism with functional differentiated cells capable of maintaining that tissue's (or organ's) original function. Damage and error accumulation in genetic material is always a problem for systems regardless of the age.Antileukemic drug: Antileukemic drugs, anticancer drugs that are used to treat one or more types of leukemia, include:Blood cell: A blood cell, also called a hemocyte, hematocyte, or hematopoietic cell, is a cell produced through hematopoiesis and is normally found in blood. In mammals, these fall into three general categories:CytarabineGreat Recession in Africa: As a direct result of the late 2000s recession, some economies in Africa have been primarily affected by reduced global demand and lower prices of commodities such as oil, platinum, nickel, gold, and copper. South Africa was the first African country to fall in recession.Granulocyte: framed|Eosinophilic granulocyteGenetic 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.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.Myeloid: 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.Sickle-cell diseaseRefractory cytopenia with multilineage dysplasiaTyrosine-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.Oncogene: An oncogene is a gene that has the potential to cause cancer.Wilbur, Beth, editor.Myelodysplastic–myeloproliferative diseases: Myelodysplastic–myeloproliferative diseases are a category of hematological malignancies disorders created by the World Health Organization which have characteristics of both myelodysplastic and myeloproliferative conditions.Bone 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.SurE, survival protein E: In molecular biology, the protein domain surE refers to survival protein E. It was originally found that cells that did not contain this protein, could not survive in the stationary phase, at above normal temperatures, and in high-salt media.Cancer/testis antigen family 45, member a5Benzo(c)phenanthreneTumor progression: Tumor progression is the third and last phase in tumor development. This phase is characterised by increased growth speed and invasiveness of the tumor cells.Intraepithelial lymphocyte: Intraepithelial lymphocytes (IEL) are lymphocytes found in the epithelial layer of mammalian mucosal linings, such as the gastrointestinal (GI) tract and reproductive tract. However, unlike other T cells, IELs do not need priming.Silent mutation: Silent mutations are mutations in DNA that do not significantly alter the phenotype of the organism in which they occur. Silent mutations can occur in non-coding regions (outside of genes or within introns), or they may occur within exons.Immunophenotyping: Immunophenotyping is a technique used to study the protein expressed by cells. This technique is commonly used in basic science research and laboratory diagnostic purpose.Adenosine deaminase deficiencyColes PhillipsWeedy rice: Weedy rice, also known as red rice, is a variety of rice (Oryza) that produces far fewer grains per plant than cultivated rice and is therefore considered a pest. The name "weedy rice" is used for all types and variations of rice which show some characteristic features of cultivated rice and grow as weeds in commercial rice fields.Polyclonal B cell response: Polyclonal B cell response is a natural mode of immune response exhibited by the adaptive immune system of mammals. It ensures that a single antigen is recognized and attacked through its overlapping parts, called epitopes, by multiple clones of B cell.Toronto propane explosionSymmetry 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.Thiazoline
(1/479) Toward a leukemia treatment strategy based on the probability of stem cell death: an essay in honor of Dr. Emil J Freireich.
Dr. Emil J Freireich is a pioneer in the rational treatment of cancer in general and leukemia in particular. This essay in his honor suggests that the cell kill concept of chemotherapy of acute myeloblastic leukemia be extended to include two additional ideas. The first concept is that leukemic blasts, like normal hemopoietic cells, are organized in hierarchies, headed by stem cells. In both normal and leukemic hemopoiesis, killing stem cells will destroy the system; furthermore, both normal and leukemic cells respond to regulators. It follows that acute myelogenous leukemia should be considered as a dependent neoplasm. The second concept is that cell/drug interaction should be considered as two phases. The first, or proximal phase, consists of the events that lead up to injury; the second, or distal phase, comprises the responses of the cell that contribute to either progression to apoptosis or recovery. Distal responses are described briefly. Regulated drug sensitivity is presented as an example of how distal responses might be used to improve treatment. (+info)
(2/479) Prognostic significance of bone marrow biopsy in essential thrombocythemia.
BACKGROUND AND OBJECTIVE: The diagnostic and prognostic value of bone marrow biopsy (BMB) has been widely investigated in patients with chronic myeloproliferative disorders (CMPD). The present study is based on a review of the results of routine BMBs taken from 93 essential thrombocythemia (ET) patients at the time of diagnosis. DESIGN AND METHODS: The common BMB histologic parameters and clinico-hematologic variables were considered for diagnostic and prognostic purposes. Clinico-pathologic correlations were looked for univariately. Moreover, the diagnostic significance of the histologic findings was tested by means of cluster analysis. Overall survival and event-free survival were considered as prognostic endpoints. RESULTS: There were no correlations between the clinic and pathologic findings, and none of the histologic and clinical parameters was predictive of survival or the occurrence of major clinical events. Cluster analysis of the BMB findings revealed two distinct morphologic patterns: one was clearly myeloproliferative; the other had somewhat dysplastic features. The event-free and overall survival rates in the latter group were significantly worse (p = 0.0377 and p = 0.0162 respectively), with major ischemic events accounting for most of the difference in event-free survival. INTERPRETATION AND CONCLUSIONS: These results have no clearcut counterpart in the literature, but we feel that dysplastic BMB findings could be included in the definition of ET prognostic scores in order to allow therapeutic strategies to be adapted to the level of risk. (+info)
(3/479) Increased BAX expression is associated with an increased risk of relapse in childhood acute lymphocytic leukemia.
Studies in cell lines have indicated that expression of the BCL-2 family of proteins is an important determinant of chemotherapy-induced apoptosis; however, the level of expression of these proteins in childhood acute lymphoblastic leukemia (ALL) has not been extensively reported. Using quantitative Western blotting we have determined the level of expression of BCL-2, BAX, MCL-1, and BCL-X in lymphoblasts from 47 children with ALL (33 at presentation only, 4 at relapse only, and 10 at both presentation and on relapse). Results were determined as a ratio to actin as an internal control. BCL-2, BAX, and MCL-1 were detected in all samples. BCL-XL was only detected in 6 cases (4 at presentation and 2 at relapse) and BCL-XS in none. No correlation was found between expression and white blood cell count, age at diagnosis, gender, or blast karyotype. BCL-2 levels and the BCL/BAX and MCL-1/BAX ratios were found to be significantly higher in B-lineage as compared with T-lineage disease (P <.003,.02, and.02, respectively). No consistent pattern of change in expression was noted in the 10 cases studied at both presentation and relapse. Kaplan-Meier analysis showed a significant correlation between high BAX expression and an increased probability of relapse (P <.05 by the log rank test), suggesting that chemosensitivity in leukemic blasts may be regulated by factors that override the BCL-2 pathway. (+info)
(4/479) Matrix metalloproteinase production by bone marrow mononuclear cells from normal individuals and patients with acute and chronic myeloid leukemia or myelodysplastic syndromes.
The two matrix metalloproteinases (MMPs) Mr 72,000 type IV collagenase (MMP-2, gelatinase A) and Mr 92,000 type IV collagenase (MMP-9, gelatinase B) play key roles in tissue remodeling and tumor invasion by digestion of extracellular matrix barriers. We have investigated the production of these two enzymes as well as the membrane-type MMP (MT1-MMP) and the tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 in the bone marrow mononuclear cells (BM-MNCs) of patients with acute myeloid leukemia (AML; n = 24), chronic myeloid leukemia (CML; n = 17), myelodysplastic syndromes (MDS; n = 8), and healthy donors (n = 5). Zymographic analysis of BM-MNC-conditioned medium showed that a Mr 92,000 gelatinolytic activity, identified as MMP-9 by Western blotting, was constitutively released from cells of all patients and healthy individuals examined in this study. In contrast, MMP-2 secretion was found to be absent in all samples from healthy donors but present in 8 of 11 (73%) of the samples from patients with primary AML, 7 of 8 (88%) with secondary AML, and only 1 of 5 (20%) cases with AML in remission, indicating MMP-2 to be produced by the leukemic blasts. MMP-2 release was not detected in CML cell-conditioned medium with the exception of two cases, both patients either being in or preceding blast crisis. In MDS, MMP-2 was found in three of eight (38%) of the patients, two of them undergoing progression of disease within 12 months. Quantitative Northern blot analysis in freshly isolated BM-MNCs showed a relatively low constitutive expression of TIMP-1 in all samples, whereas MMP-9 gene transcription was higher in healthy donors and CML samples, than in AML and MDS. Reverse transcriptase-PCR analysis revealed the presence of TIMP-2 mRNA in the majority of MMP-2-releasing BM-MNCs. MT1-MMP expression was present in most samples of patients with MDS or AML but absent in those with secondary AML and CML. Thus, we have shown that BM-MNCs continuously produce MMP-9 and TIMP-1 and demonstrated that leukemic blast cells additionally secrete MMP-2 representing a potential marker for dissemination in myeloproliferative malignancies. (+info)
(5/479) Characterization of a novel receptor that maps near the natural killer gene complex: demonstration of carbohydrate binding and expression in hematopoietic cells.
A novel type II integral membrane protein has been identified in the course of screening for genes overexpressed in a mouse model of chronic myelogenous leukemia blast crisis. This new protein, designated NKCL, consists of a 210-amino acid polypeptide with a short, NH2-terminal cytoplasmic tail of 17 amino acids preceding a transmembrane domain and a COOH-terminal extracellular region. The COOH-terminal 132 amino acids bear typical features of the C-type animal lectin carbohydrate-recognition domain. The Nkcl gene is unique in that it maps just proximal to the region of the genome that encodes group V members of the C-type animal lectin family near the natural killer gene complex on mouse chromosome 6, but its protein product also has features of several group II C-type animal lectins. Most notably, it has a complete Ca2+-binding site 2, which forms part of the sugar-binding site in other members of the family, and binds mannose in a Ca2+-dependent manner. Moreover, its expression is not restricted to natural killer cells, as reported for the majority of group V lectins. Nkcl is expressed in pluripotent myeloid precursors, precursor and mature macrophages, and neutrophils. (+info)
(6/479) Thiotepa, busulfan and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced chronic myelogenous leukemia.
Thirty-six adults with chronic myelogenous leukemia (CML) in second or greater chronic phase, accelerated phase, or blast crisis underwent marrow or blood stem cell transplantation from an HLA-matched sibling using high-dose thiotepa, busulfan and cyclophosphamide (TBC) as the preparative regimen. All evaluable patients engrafted and had complete donor chimerism. One patient failed to clear meningeal leukemia, and one patient had one of 30 metaphases positive for the Philadelphia chromosome at 2 months post transplant. The remainder of the patients studied had eradication of CML documented by cytogenetics and/or Southern blot for BCR gene rearrangement, and 13 of 15 patients studied became negative for the BCR gene rearrangement by polymerase chain reaction. Three-year relapse rate is 42% (95% CI, 19-64%). The relapse rate was significantly lower for patients transplanted without blast crisis (9% vs 100%, P < 0.001). Eight (22%, 95% CI, 10-39%) patients had severe or fatal veno-occlusive disease (VOD). Elevated liver enzymes within 1 month prior to transplantation and transplantation using marrow were significantly associated with the occurrence of VOD. Three-year survival is 28% (95% CI, 13-43%). Survival was significantly higher for patients transplanted without blast crisis (45% vs 0%, P = 0.01). TBC is an effective preparative regimen for CML in accelerated phase but not refractory blast crisis, and it should be used with caution in patients with prior hepatopathy who have an increased risk of severe VOD. (+info)
(7/479) Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia.
Gene targeting studies in mice have shown that the lack of Ikaros activity leads to T-cell hyperproliferation and T-cell neoplasia, establishing the Ikaros gene as a tumor suppressor gene in mice. This prompted us to investigate whether mutations in Ikaros play a role in human hematological malignancies. Reverse transcription-PCR was used to determine the relative expression levels of Ikaros isoforms in a panel of human leukemia/lymphoma cell lines and human bone marrow samples from patients with hematological malignancies. Among the cell lines examined, only BV-173, which was derived from a chronic myelogenous leukemia (CML) patient in lymphoid blast crisis, overexpressed the dominant-negative isoform, Ik-6. In 9 of 17 samples of patients in blast crisis of CML, Ikaros activity had been reduced either by drastically reducing mRNA expression (4 of 17) or by overexpressing the dominant-negative isoform Ik-6 (5 of 17). Significantly, expression of Ikaros isoforms seemed normal in chronic phase CML patients and patients with other hematological malignancies. In some cases, overexpression of the dominant-negative Ik-6 protein was confirmed by Western blot analysis, and Southern blot analysis indicated that decreases in Ikaros activity correlated with a mutation in the Ikaros locus. In summary, these findings suggest that a reduction of Ikaros activity may be an important step in the development of blast crisis in CML and provide further evidence that mutations that alter Ikaros expression may contribute to human hematological malignancies. (+info)
(8/479) Triggering noncycling hematopoietic progenitors and leukemic blasts to proliferate increases anthracycline retention and toxicity by downregulating multidrug resistance.
Expression of the multidrug resistance (MDR) mechanisms P-glycoprotein (Pgp) and MDR-related protein (MRP) decrease cellular retention and consequently cytotoxicity of anthracyclines. MDR is expressed on normal human hematopoietic progenitors and leukemic blasts. Normal CD34(+) progenitors showed rhodamine efflux in 20% to 30% of the cells, which could be blocked by verapamil. These cells appeared noncycling, in contrast to the proliferating rhodamine bright (RhoB) cells. We postulated that MDR expression can be downregulated by proliferation induction. Triggering rhodamine dull (RhoD) CD34(+) cells to proliferate indeed resulted in a higher rhodamine retention and significantly decreased efflux modulation by verapamil (P =.04). Also in acute myeloid leukemia (AML), the proliferation rate (percentage S/G(2)+M and Iododeoxyuridine labelings index) was significantly less in the RhoD blasts (P =. 008) and proliferation induction of RhoD blasts resulted in increased rhodamine retention. Anthracycline cytotoxicity was less for RhoD than RhoB cells in both normal progenitors and leukemic blasts. Proliferation induction of the RhoD cells resulted in increased anthracycline sensitivity. We conclude that noncycling progenitors, both normal and leukemic, have a relatively high MDR expression. Triggering these cells into proliferation downregulates MDR expression. These findings can be exploited to overcome MDR in the treatment of AML patients. (+info)