BCR-ABL down-regulates the DNA repair protein DNA-PKcs

• Published in: Blood 2001-04, Vol.97 (7), p.2084-2090
• Main Authors: Deutsch, Eric, Dugray, Aymeric, AbdulKarim, Bassam, Marangoni, Elisabetta, Maggiorella, Laurence, Vaganay, Sabine, M'Kacher, Radia, Rasy, Setha Douc, Eschwege, François, Vainchenker, William, Turhan, Ali G., Bourhis, Jean
• Format: Article
• Language: English
• Subjects: Acetylcysteine - analogs & derivatives; Acetylcysteine - pharmacology; Animals; Apoptosis - genetics; Apoptosis - radiation effects; Biological and medical sciences; Blast Crisis - genetics; Child; Cysteine Endopeptidases - metabolism; DNA Repair - genetics; DNA, Neoplasm - metabolism; DNA-Activated Protein Kinase; DNA-Binding Proteins; Enzyme Induction; Enzyme Inhibitors - pharmacology; Fusion Proteins, bcr-abl - physiology; Gene Expression Regulation, Leukemic; Hematologic and hematopoietic diseases; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - metabolism; Neuroblastoma - pathology; Nuclear Proteins; Oligopeptides - pharmacology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protease Inhibitors - pharmacology; Proteasome Endopeptidase Complex; Protein-Serine-Threonine Kinases - biosynthesis; Protein-Serine-Threonine Kinases - genetics; Recombinant Fusion Proteins - physiology; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Tumor Cells, Cultured - enzymology; Tumor Stem Cell Assay; Tyrphostins - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V97.7.2084

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.