Abstract
This study demonstrates in both stable and inducible BCR-ABL-expressing hematopoietic cells a down-regulation of the major mammalian DNA repair protein DNA-PKcs by BCR-ABL. Similar results were found in BCR-ABL CD34(+) cells from patients with chronic myelogenous leukemia (CML). DNA-PKcs down-regulation is a proteasome-dependent degradation that requires tyrosine kinase activity and is associated with a marked DNA repair deficiency along with increased sensitivity to ionizing radiation. The conjunction of a major DNA repair deficiency and a resistance to apoptosis, both induced by BCR-ABL, provides a new mechanism to explain how secondary genetic alterations can accumulate in CML, eventually leading to blast crisis. The down-regulation of DNA-PKcs was reversible in CD34(+) CML cells suggesting that this approach might offer a novel and powerful therapeutic strategy in this disease, especially to delay the blast crisis. (Blood. 2001;97:2084-2090)
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / analogs & derivatives*
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Acetylcysteine / pharmacology
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Animals
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Apoptosis / genetics
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Apoptosis / radiation effects
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Blast Crisis / genetics
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Child
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Cysteine Endopeptidases / metabolism
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DNA Repair / genetics*
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DNA, Neoplasm / metabolism
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DNA-Activated Protein Kinase
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DNA-Binding Proteins*
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Enzyme Induction
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Enzyme Inhibitors / pharmacology
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Fusion Proteins, bcr-abl / physiology*
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Gene Expression Regulation, Leukemic*
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Humans
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In Situ Hybridization, Fluorescence
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Mice
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Multienzyme Complexes / antagonists & inhibitors
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Multienzyme Complexes / metabolism
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Neuroblastoma / pathology
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Nuclear Proteins
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Oligopeptides / pharmacology
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Protease Inhibitors / pharmacology
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Proteasome Endopeptidase Complex
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics*
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Recombinant Fusion Proteins / physiology
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Reverse Transcriptase Polymerase Chain Reaction
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Transfection
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Tumor Cells, Cultured / enzymology
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Tumor Stem Cell Assay
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Tyrphostins / pharmacology
Substances
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DNA, Neoplasm
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DNA-Binding Proteins
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Enzyme Inhibitors
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Multienzyme Complexes
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Nuclear Proteins
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Oligopeptides
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Protease Inhibitors
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Recombinant Fusion Proteins
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Tyrphostins
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tyrphostin AG957
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lactacystin
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Fusion Proteins, bcr-abl
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DNA-Activated Protein Kinase
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PRKDC protein, human
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Protein Serine-Threonine Kinases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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Acetylcysteine