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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3150-3159. Prepublished online as a Blood First Edition Paper on July 12, 2005; DOI 10.1182/blood-2005-02-0553. This Article Full Text (PDF) All Versions of this Article: 2005-02-0553v1 106/9/3150    most recent Alert me when this article is cited Alert me if a correction is posted 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 9, 2005 Accepted June 22, 2005 MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy Kensuke Kojima, Marina Konopleva, Ismael J Samudio, Masato Shikami, Maria Cabreira-Hansen, Teresa McQueen, Vivian Ruvolo, Twee Tsao, Zhihong Zeng, Lyubomir T Vassilev, and Michael Andreeff* Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Discovery Oncology, Roche Research Center, Hoffman-La Roche, Inc., Nutley, New Jersey, USA * Corresponding author; email: mandreef{at}mdanderson.org. Although TP53 mutations are rare in acute myeloid leukemia (AML), inactivation of wild-type p53 protein frequently occurs through overexpression of its negative regulator MDM2. Recently, small-molecule antagonists of MDM2, Nutlins, have been developed that inhibit the p53-MDM2 interaction and activate p53 signaling. Here, we study the effects of p53 activation by Nutlin-3 in AML cells. Treatment with MDM2 inhibitor triggered several molecular events consistent with induction of apoptosis: loss of mitochondrial membrane potential, caspase activation, phosphatidylserine externalization and DNA fragmentation. There was a positive correlation in primary AML samples with wild-type p53 between baseline MDM2 protein levels and apoptosis induced by MDM2 inhibition. No induction of apoptosis was observed in AML samples harboring mutant p53. Colony formation of AML progenitors was inhibited in a dose-dependent fashion, whereas normal CD34+ progenitor cells were less affected. Mechanistic studies suggested that Nutlin-induced apoptosis was mediated by both transcriptional activation of proapoptotic Bcl-2 family proteins, and transcription-independent mitochondrial permeabilization resulting from mitochondrial p53 translocation. MDM2 inhibition synergistically enhanced cytotoxicity of cytosine arabinoside and doxorubicin in AML blasts but not in normal hematopoietic progenitor cells. p53 activation by targeting the p53-MDM2 interaction might offer a novel therapeutic strategy for AML that retain wild-type p53. 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] M. Miyachi, N. Kakazu, S. Yagyu, Y. Katsumi, S. Tsubai-Shimizu, K. 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