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Expression of p210 bcr/abl increases hematopoietic progenitor cell radiosensitivity. 1993

M A Santucci, and P Anklesaria, and P Laneuville, and I J Das, and M A Sakakeeny, and T J FitzGerald, and J S Greenberger
Department of Radiation Oncology, University of Massachusetts Medical Center, Worcester 01655.

OBJECTIVE The cytogenetic finding of the Ph1+ chromosome and its molecular biologic marker bcr/abl gene rearrangement in cells from patients with chronic myeloid leukemia are associated with a proliferative advantage of the Ph1+ clone in vivo. Although the transition to the acute terminal phase or blastic crisis is often associated with additional cytogenetic abnormalities, the molecular events which correlate the initial cytogenetic lesion with the terminal phase are poorly understood. Defective cellular DNA repair capacity is often associated with chromosomal instability, increased mutation frequency, and biologic alterations. METHODS We, therefore, tested whether the protein product of the bcr/abl translocation (p210) could alter DNA repair after gamma-irradiation of murine cell lines expressing the bcr/abl cDNA. RESULTS The 32D cl 3 parent, 32D cl 3 pYN (containing the control vector plasmid) and each of two sources of 32D cl 3 cells expressing p210 bcr/abl cDNA (32D-PC1 cell line and 32D-LG7 subclone) showed a D0 of 1.62, 1.57, 1.16, and 1.27 Gy, respectively. Thus, expression of the p210 bcr/abl product induced a significant (p < 0.05) increase in radiosensitivity at the clinically relevant radiation therapy dose-rate (1.16 Gy/min). The increased radiosensitivity of p210 bcr/abl expressing cells persisted if cells were held before plating in a density-inhibited state for 8 hr after gamma-irradiation, indicating little effect on the repair of potentially lethal gamma-irradiation damage. The IL-3 dependent parent 32D cl 3 cells demonstrated programmed cell death in the absence of growth factor or following gamma-irradiation to 200 cGy. Expression of bcr/abl cDNA in the 32D-PC1 and 32D-LG7 sub clones abrogated IL-3 requirement of these cell lines and inhibited gamma-irradiation induced programmed cell death. CONCLUSIONS These data suggest a role for bcr/abl p210 in amplifying gamma-irradiation DNA damage or broadly inhibiting DNA repair, conditions that may stimulate further cytogenetic alterations in hematopoietic cells.

UI MeSH Term Description Entries
D010677 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). Ph1 Chromosome,Ph 1 Chromosome,1 Chromosomes, Ph,Chromosome, Ph 1,Chromosome, Ph1,Chromosome, Philadelphia,Chromosomes, Ph 1,Chromosomes, Ph1,Ph 1 Chromosomes,Ph1 Chromosomes
D011518 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. Cellular Proto-Oncogene Proteins,c-onc Proteins,Proto Oncogene Proteins, Cellular,Proto-Oncogene Products, Cellular,Cellular Proto Oncogene Proteins,Cellular Proto-Oncogene Products,Proto Oncogene Products, Cellular,Proto Oncogene Proteins,Proto-Oncogene Proteins, Cellular,c onc Proteins
D011831 Radiation Genetics A subdiscipline of genetics that studies RADIATION EFFECTS on the components and processes of biological inheritance. Genetics, Radiation
D011836 Radiation Tolerance The ability of some cells or tissues to survive lethal doses of IONIZING RADIATION. Tolerance depends on the species, cell type, and physical and chemical variables, including RADIATION-PROTECTIVE AGENTS and RADIATION-SENSITIZING AGENTS. Radiation Sensitivity,Radiosensitivity,Sensitivity, Radiation,Tolerance, Radiation,Radiation Sensitivities,Radiation Tolerances,Radiosensitivities,Sensitivities, Radiation,Tolerances, Radiation
D004260 DNA Repair The removal of DNA LESIONS and/or restoration of intact DNA strands without BASE PAIR MISMATCHES, intrastrand or interstrand crosslinks, or discontinuities in the DNA sugar-phosphate backbones. DNA Damage Response
D006412 Hematopoietic Stem Cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Colony-Forming Units, Hematopoietic,Progenitor Cells, Hematopoietic,Stem Cells, Hematopoietic,Hematopoietic Progenitor Cells,Cell, Hematopoietic Progenitor,Cell, Hematopoietic Stem,Cells, Hematopoietic Progenitor,Cells, Hematopoietic Stem,Colony Forming Units, Hematopoietic,Colony-Forming Unit, Hematopoietic,Hematopoietic Colony-Forming Unit,Hematopoietic Colony-Forming Units,Hematopoietic Progenitor Cell,Hematopoietic Stem Cell,Progenitor Cell, Hematopoietic,Stem Cell, Hematopoietic,Unit, Hematopoietic Colony-Forming,Units, Hematopoietic Colony-Forming
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D014178 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. Chromosomal Translocation,Translocation, Chromosomal,Chromosomal Translocations,Genetic Translocation,Genetic Translocations,Translocations, Chromosomal,Translocations, Genetic
D015415 Biomarkers Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, ENVIRONMENTAL EXPOSURE and its effects, disease diagnosis; METABOLIC PROCESSES; SUBSTANCE ABUSE; PREGNANCY; cell line development; EPIDEMIOLOGIC STUDIES; etc. Biochemical Markers,Biological Markers,Biomarker,Clinical Markers,Immunologic Markers,Laboratory Markers,Markers, Biochemical,Markers, Biological,Markers, Clinical,Markers, Immunologic,Markers, Laboratory,Markers, Serum,Markers, Surrogate,Markers, Viral,Serum Markers,Surrogate Markers,Viral Markers,Biochemical Marker,Biologic Marker,Biologic Markers,Clinical Marker,Immune Marker,Immune Markers,Immunologic Marker,Laboratory Marker,Marker, Biochemical,Marker, Biological,Marker, Clinical,Marker, Immunologic,Marker, Laboratory,Marker, Serum,Marker, Surrogate,Serum Marker,Surrogate End Point,Surrogate End Points,Surrogate Endpoint,Surrogate Endpoints,Surrogate Marker,Viral Marker,Biological Marker,End Point, Surrogate,End Points, Surrogate,Endpoint, Surrogate,Endpoints, Surrogate,Marker, Biologic,Marker, Immune,Marker, Viral,Markers, Biologic,Markers, Immune
D015464 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. Granulocytic Leukemia, Chronic,Leukemia, Granulocytic, Chronic,Leukemia, Myelocytic, Chronic,Leukemia, Myelogenous, Chronic,Leukemia, Myeloid, Chronic,Myelocytic Leukemia, Chronic,Myelogenous Leukemia, Chronic,Myeloid Leukemia, Chronic,Leukemia, Chronic Myelogenous,Leukemia, Chronic Myeloid,Leukemia, Myelogenous, Ph1 Positive,Leukemia, Myelogenous, Ph1-Positive,Leukemia, Myeloid, Ph1 Positive,Leukemia, Myeloid, Ph1-Positive,Leukemia, Myeloid, Philadelphia Positive,Leukemia, Myeloid, Philadelphia-Positive,Myelogenous Leukemia, Ph1-Positive,Myeloid Leukemia, Ph1-Positive,Myeloid Leukemia, Philadelphia-Positive,Chronic Granulocytic Leukemia,Chronic Granulocytic Leukemias,Chronic Myelocytic Leukemia,Chronic Myelocytic Leukemias,Chronic Myelogenous Leukemia,Chronic Myelogenous Leukemias,Chronic Myeloid Leukemia,Chronic Myeloid Leukemias,Granulocytic Leukemias, Chronic,Leukemia, Chronic Granulocytic,Leukemia, Chronic Myelocytic,Leukemia, Ph1-Positive Myelogenous,Leukemia, Ph1-Positive Myeloid,Leukemia, Philadelphia-Positive Myeloid,Leukemias, Chronic Granulocytic,Leukemias, Chronic Myelocytic,Leukemias, Chronic Myelogenous,Leukemias, Chronic Myeloid,Leukemias, Ph1-Positive Myelogenous,Leukemias, Ph1-Positive Myeloid,Leukemias, Philadelphia-Positive Myeloid,Myelocytic Leukemias, Chronic,Myelogenous Leukemia, Ph1 Positive,Myelogenous Leukemias, Chronic,Myelogenous Leukemias, Ph1-Positive,Myeloid Leukemia, Ph1 Positive,Myeloid Leukemia, Philadelphia Positive,Myeloid Leukemias, Chronic,Myeloid Leukemias, Ph1-Positive,Myeloid Leukemias, Philadelphia-Positive,Ph1-Positive Myelogenous Leukemia,Ph1-Positive Myelogenous Leukemias,Ph1-Positive Myeloid Leukemia,Ph1-Positive Myeloid Leukemias,Philadelphia-Positive Myeloid Leukemia,Philadelphia-Positive Myeloid Leukemias

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