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Blood, 1 August 2006, Vol. 108, No. 3, pp. 993-1000. Prepublished online as a Blood First Edition Paper on March 16, 2006; DOI 10.1182/blood-2005-12-5148. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-12-5148v1 108/3/993    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 Kojima, K. Articles by Andreeff, M. Search for Related Content PubMed PubMed Citation Articles by Kojima, K. Articles by Andreeff, M. Related Collections Neoplasia Apoptosis Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia Kensuke Kojima, Marina Konopleva, Teresa McQueen, Susan O'Brien, William Plunkett, and Michael Andreeff From the Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, the Department of Leukemia, and the Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX. Although TP53 mutations are rare in B-cell chronic lymphocytic leukemia (CLL), Mdm2 overexpression has been reported as an alternative cause of p53 dysfunction. We investigated the potential therapeutic use of nongenotoxic p53 activation by a small-molecule antagonist of Mdm2, Nutlin-3a, in CLL. Nutlin-3a induced significant apoptosis in 30 (91%) of 33 samples from previously untreated patients with CLL; all resistant samples had TP53 mutations. Low levels of Atm (ataxia telangiectasia mutated) or high levels of Mdm2 (murine double minute 2) did not prevent Nutlin-3a from inducing apoptosis. Nutlin-3a used transcription-dependent and transcription-independent pathways to induce p53-mediated apoptosis. Predominant activation of the transcription-independent pathway induced more pronounced apoptosis than that of the transcription-dependent pathway, suggesting that activation of the transcription-independent pathway is sufficient to initiate p53-mediated apoptosis in CLL. Combination treatment of Nutlin-3a and fludarabine synergistically increased p53 levels, and induced conformational change of Bax and apoptosis in wild-type p53 cells but not in cells with mutant p53. The synergistic apoptotic effect was maintained in samples with low Atm that were fludarabine resistant. Results suggest that the nongenotoxic activation of p53 by targeting the Mdm2-p53 interaction provides a novel therapeutic strategy for CLL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Lunghi, A. Costanzo, L. Mazzera, V. Rizzoli, M. Levrero, and A. Bonati The p53 Family Protein p73 Provides New Insights into Cancer Chemosensitivity and Targeting Clin. Cancer Res., November 1, 2009; 15(21): 6495 - 6502. [Abstract] [Full Text] [PDF] W. Du, J. Wu, E. M. Walsh, Y. Zhang, C. Y. Chen, and Z.-X. J. 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