BCR-ABL down-regulates the DNA repair protein DNA-PKcs.
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)
Deutsch
E
E
UPRES EA 27-10 Radiosensibilité-Radiocarcinogenèse Humaine and METSI, Institut Gustave Roussy, Villejuif, France.
Dugray
A
A
AbdulKarim
B
B
Marangoni
E
E
Maggiorella
L
L
Vaganay
S
S
M'Kacher
R
R
Rasy
S D
SD
Eschwege
F
F
Vainchenker
W
W
Turhan
A G
AG
Bourhis
J
J
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D001752:Blast Crisis / Q000235:genetics; D002648:Child; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000378:metabolism; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009687:Nuclear Proteins; D009842:Oligopeptides / Q000494:pharmacology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000201:enzymology; D014410:Tumor Stem Cell Assay; D020032:Tyrphostins / Q000494:pharmacology
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D009842:Oligopeptides; D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; D020032:Tyrphostins; C104965:tyrphostin AG957; C067713:lactacystin; D016044:Fusion Proteins, bcr-abl; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine