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Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the non-homologous end-joining DNA repair pathway
- Source :
- Blood, Blood, American Society of Hematology, 2005, 105, pp.4076-4083
- Publication Year :
- 2005
- Publisher :
- HAL CCSD, 2005.
-
Abstract
- Nonhomologous end-joining (NHEJ) DNA factors maintain genomic stability through their DNA double-strand break (DSB) repair and telomere-associated activities. Unrepaired or misrepaired DSBs can lead to apoptotic death or chromosomal damage. The B cells of some B-chronic lymphocytic leukemia (B-CLL) patients are resistant to radiation-induced apoptosis in vitro. We show here that the novel DNA-dependent protein kinase (DNA-PK) inhibitor, NU7026 (2-(morpholin-4-yl)-benzo[h]chomen-4-one), and the phosphatidylinositol 3 (PI-3) kinase inhibitor, wortmannin, restored sensitivity to DNA damage-induced apoptosis of otherwise resistant cells. These resistant malignant B cells also escaped DSB-induced apoptosis following exposure to etoposide or neocarzinostatin. We found that at 15 minutes after irradiation, the levels of NHEJ (as measured by an in vitro DSB end-ligation assay) and DNA-PK catalytic subunit (DNA-PKcs) activity were, respectively, 2-fold and 4-fold higher in radio-resistant than in radio-sensitive B-CLL cells or Epstein-Barr virus (EBV)-transformed B cells. Ku70/Ku80 heterodimer DNA end-binding activity was also 2- to 3-fold higher in the resistant B-CLL cell subset compared with the sensitive B-CLL cell subset. Our results provide the first evidence that overactivating the NHEJ DNA repair pathway impairs DNA damage-induced apoptosis in malignant B cells and that this may contribute to their resistance to current chemotherapy. (Blood. 2005;105:4776-4783)
- Subjects :
- Time Factors
Ku80
DNA Repair
Apoptosis
Biochemistry
Wortmannin
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
0302 clinical medicine
Zinostatin
Enzyme Inhibitors
Cell Line, Transformed
Etoposide
B-Lymphocytes
0303 health sciences
Ku70
Antibiotics, Antineoplastic
Antigens, Nuclear
Hematology
Telomere
DNA repair protein XRCC4
3. Good health
DNA-Binding Proteins
030220 oncology & carcinogenesis
Dimerization
Protein Binding
DNA repair
DNA damage
Morpholines
Blotting, Western
Immunology
[SDV.CAN]Life Sciences [q-bio]/Cancer
Biology
03 medical and health sciences
Cell Line, Tumor
Okadaic Acid
Humans
Ku Autoantigen
030304 developmental biology
Cell-Free System
Dose-Response Relationship, Drug
DNA
Cell Biology
DNA Repair Pathway
Antineoplastic Agents, Phytogenic
Leukemia, Lymphocytic, Chronic, B-Cell
Molecular biology
Proliferating cell nuclear antigen
Androstadienes
chemistry
Chromones
Gamma Rays
Cancer research
biology.protein
DNA Damage
Subjects
Details
- Language :
- English
- ISSN :
- 47764783, 00064971, and 15280020
- Database :
- OpenAIRE
- Journal :
- Blood, Blood, American Society of Hematology, 2005, 105, pp.4076-4083
- Accession number :
- edsair.doi.dedup.....7cc6978f2cacdcb6c85a4817b629a286