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Prepublished online as a Blood First Edition Paper on April 17, 2003; DOI 10.1182/blood-2002-11-3429. This Article Full Text (PDF) All Versions of this Article: 2002-11-3429v1 102/3/972    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 Xu, Q. Articles by Carroll, M. Search for Related Content PubMed PubMed Citation Articles by Xu, Q. Articles by Carroll, M. Social Bookmarking                   What's this? Submitted November 20, 2002 Accepted February 24, 2003 Survival of acute myeloid leukemia cells requires PI3 kinase activation Qing Xu, Serge-Emile Simpson, Timothy J Scialla, Adam Bagg, and Martin Carroll* Division of Hematology/Oncology, University of Pennsylvania, Philadlephia, PA, USA Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA * Corresponding author; email: carroll2{at}mail.med.upenn.edu. The mechanisms that regulate the growth and survival of acute myeloid leukemia (AML) cells are largely unknown. We hypothesized that constitutive activation of phosphatidyl-inositide 3 kinase (PI3 kinase) could regulate survival in primary cells from patients with AML. Here we demonstrate that Akt, a critical substrate of PI3 kinase, is activated in AML blasts. In a short term culture system, the majority of AML patient samples showed a dose dependent decrease in survival after incubation with the PI3 kinase inhibitor, LY294002. This decrease in survival was partially due to the induction of apoptosis. Furthermore, we have shown that p70 S6 kinase and 4EBP-1, downstream mediators of Akt signaling, are also phosphorylated in AML blasts. Phosphorylation of these proteins is inhibited by the mTOR inhibitor, RAD001. Incubation of AML blasts with RAD001 induces only a small decrease in survival of the cells however, when combined with Ara-C, RAD001 enhances the toxicity of Ara-C. These results demonstrate that constitutive activation of the PI3 kinase pathway is necessary for the survival of AML blasts and that targeting of this pathway with pharmacologic inhibitors may be of clinical benefit in treatment of AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Rahmani, A. Anderson, J. R. Habibi, T. R. Crabtree, M. Mayo, H. Harada, A. Ferreira-Gonzalez, P. Dent, and S. 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