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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. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 2004-07-2888v1 105/12/4776    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Deriano, L. Articles by Delic, J. Search for Related Content PubMed PubMed Citation Articles by Deriano, L. Articles by Delic, J. Related Collections Neoplasia Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  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) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Willmore, S. L. Elliott, T. Mainou-Fowler, G. P. Summerfield, G. H. Jackson, F. O'Neill, C. Lowe, A. Carter, R. Harris, A. R. Pettitt, et al. 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