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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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NEOPLASIA
Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway
Ludovic Deriano,
Olivier Guipaud,
Hélène Merle-Béral,
Jacques-Louis Binet,
Michelle Ricoul,
Gaby Potocki-Veronese,
Vincent Favaudon,
Zofia Maciorowski,
Catherine Muller,
Bernard Salles,
Laure Sabatier, and
Jozo Delic
From the Laboratoire de Radiobiologie et Oncologie, Commissariat à l'Enegie Atomique, Fontenay-aux-Roses, France; the Département d'Hématologie, Unité Claude Bernard C20, Hôpital Pitié-Salpêtrière, Paris, France; Institut Curie, Section de Recherche (Institut National de la Santé et de la Recherche Médicale [INSERM] U612), Centre Universitaire, Orsay Cedex and Laboratoire de Cytométrie, Section Médicale, Paris, France; and the Institut de Pharmacologie et de Biologie Structurale (Centre National de la Recherche Scientifique [CNRS] Unité Propre de Recherche [UPR] 9062), Toulouse, France.
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)
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