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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4776-4783.
Prepublished online as a Blood First Edition Paper on February 17, 2005; DOI 10.1182/blood-2004-07-2888.
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Submitted July 28, 2004
Accepted February 11, 2005
Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the non-homologous end-joining DNA repair pathway
Ludovic DERIANO, Olivier GUIPAUD, Helene MERLE-BERAL, Jacques-Louis BINET, Michelle RICOUL, Gaby POTOCKI-VERONESE, Vincent FAVAUDON, Zofia MACIOROWSKI, Catherine MULLER, Bernard SALLES, Laure SABATIER, and Jozo DELIC*
Laboratoire de Radiobiologie et Oncologie, Commissariat a l'Enegie Atomique, Fontenay aux Roses, France
Department d'Hematologie, Unite Claude Bernard C20, Hopital Pitie-Salpetriere, Paris, France
Institut Curie, Section de Recherche (INSERM U612), Centre Universitaire, Orsay Cedex and Laboratoire de Cytometrie, Section Medicale 26, Paris, France
Institut de Pharmacologie et de Biologie Structurale (CNRS UPR 9062), Toulouse, France
* Corresponding author; email: jozo.delic{at}cea.fr.
Non-homologous 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-PK inhibitor, NU7026 (2-(morpholin-4-yl)-benzo[h]chomen-4-one), and the 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 post-irradiation the levels of NHEJ (as measured by an in vitro DSB end-ligation assay) and DNA-PKcs activity were respectively two-fold and four-fold higher in radio-resistant than in radio-sensitive B-CLL cells or EBV-transformed B cells. Ku70/Ku80 heterodimer DNA end-binding activity was also two- to three-fold higher in the resistant B-CLL cell subset compared to in 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.
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