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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 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 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 Xu, Q. Articles by Carroll, M. Search for Related Content PubMed PubMed Citation Articles by Xu, Q. Articles by Carroll, M. Related Collections Neoplasia Apoptosis Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 August 2003, Vol. 102, No. 3, pp. 972-980 NEOPLASIA Survival of acute myeloid leukemia cells requires PI3 kinase activation Qing Xu, Serge-Emile Simpson, Timothy J. Scialla, Adam Bagg, and Martin Carroll From the Division of Hematology and Oncology and the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 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, most 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, also are 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: J. Si and S. J. 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Recher A critical role for Lyn in acute myeloid leukemia Blood, February 15, 2008; 111(4): 2269 - 2279. [Abstract] [Full Text] [PDF] A. Vasconsuelo, L. Milanesi, and R. Boland 17{beta}-Estradiol abrogates apoptosis in murine skeletal muscle cells through estrogen receptors: role of the phosphatidylinositol 3-kinase/Akt pathway J. Endocrinol., February 1, 2008; 196(2): 385 - 397. [Abstract] [Full Text] [PDF] J. Tamburini, N. Chapuis, V. Bardet, S. Park, P. Sujobert, L. Willems, N. Ifrah, F. Dreyfus, P. Mayeux, C. Lacombe, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways Blood, January 1, 2008; 111(1): 379 - 382. [Abstract] [Full Text] [PDF] J. Zhou, J. Wulfkuhle, H. Zhang, P. Gu, Y. Yang, J. Deng, J. B. Margolick, L. A. Liotta, E. Petricoin III, and Y. Zhang Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance PNAS, October 9, 2007; 104(41): 16158 - 16163. [Abstract] [Full Text] [PDF] J. Tamburini, C. Elie, V. Bardet, N. Chapuis, S. Park, P. Broet, P. Cornillet-Lefebvre, B. Lioure, V. Ugo, O. Blanchet, et al. Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients Blood, August 1, 2007; 110(3): 1025 - 1028. [Abstract] [Full Text] [PDF] Y.-L. Hu, E. Passegue, S. Fong, C. Largman, and H. J. Lawrence Evidence that the Pim1 kinase gene is a direct target of HOXA9 Blood, June 1, 2007; 109(11): 4732 - 4738. [Abstract] [Full Text] [PDF] J. M. Campistol, J. Albanell, W. Arns, I. Boletis, J. Dantal, J. W. de Fijter, S. A. Mortensen, H.-H. Neumayer, O. Oyen, J. Pascual, et al. Use of proliferation signal inhibitors in the management of post-transplant malignancies--clinical guidance Nephrol. Dial. Transplant., May 1, 2007; 22(suppl_1): i36 - i41. [Abstract] [Full Text] [PDF] A. Gutierrez-Dalmau and J. M. Campistol The role of proliferation signal inhibitors in post-transplant malignancies Nephrol. Dial. Transplant., May 1, 2007; 22(suppl_1): i11 - i16. [Abstract] [Full Text] [PDF] U. Testa and R. Riccioni Deregulation of apoptosis in acute myeloid leukemia Haematologica, January 1, 2007; 92(1): 81 - 94. [Abstract] [Full Text] [PDF] B. Ozpolat, U. Akar, M. Steiner, I. Zorrilla-Calancha, M. Tirado-Gomez, N. Colburn, M. Danilenko, S. Kornblau, and G. Lopez Berestein Programmed Cell Death-4 Tumor Suppressor Protein Contributes to Retinoic Acid-Induced Terminal Granulocytic Differentiation of Human Myeloid Leukemia Cells Mol. Cancer Res., January 1, 2007; 5(1): 95 - 108. [Abstract] [Full Text] [PDF] R. Tibes, Y. Qiu, Y. Lu, B. Hennessy, M. Andreeff, G. B. Mills, and S. M. Kornblau Reverse phase protein array: validation of a novel proteomic technology and utility for analysis of primary leukemia specimens and hematopoietic stem cells. Mol. Cancer Ther., October 1, 2006; 5(10): 2512 - 2521. [Abstract] [Full Text] [PDF] T. Ikezoe, C. Nishioka, T. Tasaka, Y. Yang, N. Komatsu, K. Togitani, H. P. Koeffler, and H. Taguchi The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol. Cancer Ther., October 1, 2006; 5(10): 2522 - 2530. [Abstract] [Full Text] [PDF] S. M. Kornblau, M. Womble, Y. H. Qiu, C. E. Jackson, W. Chen, M. Konopleva, E. H. Estey, and M. Andreeff Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia Blood, October 1, 2006; 108(7): 2358 - 2365. [Abstract] [Full Text] [PDF] C. T. Jordan, M. L. Guzman, and M. Noble Cancer stem cells. N. Engl. J. Med., September 21, 2006; 355(12): 1253 - 1261. [Full Text] [PDF] Z. Zeng, I. J. Samudio, W. Zhang, Z. Estrov, H. Pelicano, D. Harris, O. Frolova, N. Hail Jr., W. Chen, S. M. Kornblau, et al. Simultaneous Inhibition of PDK1/AKT and Fms-Like Tyrosine Kinase 3 Signaling by a Small-Molecule KP372-1 Induces Mitochondrial Dysfunction and Apoptosis in Acute Myelogenous Leukemia. Cancer Res., April 1, 2006; 66(7): 3737 - 3746. [Abstract] [Full Text] [PDF] D. Sampath, J. Cortes, Z. Estrov, M. Du, Z. Shi, M. Andreeff, V. Gandhi, and W. Plunkett Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial Blood, March 15, 2006; 107(6): 2517 - 2524. [Abstract] [Full Text] [PDF] F. Ravandi and Z. Estrov Eradication of Leukemia Stem Cells as a New Goal of Therapy in Leukemia Clin. Cancer Res., January 15, 2006; 12(2): 340 - 344. [Abstract] [Full Text] [PDF] Q. Xu, J. E. Thompson, and M. Carroll mTOR regulates cell survival after etoposide treatment in primary AML cells Blood, December 15, 2005; 106(13): 4261 - 4268. [Abstract] [Full Text] [PDF] C. H. Brandts, B. Sargin, M. Rode, C. Biermann, B. Lindtner, J. Schwable, H. Buerger, C. Muller-Tidow, C. Choudhary, M. McMahon, et al. Constitutive Activation of Akt by Flt3 Internal Tandem Duplications Is Necessary for Increased Survival, Proliferation, and Myeloid Transformation Cancer Res., November 1, 2005; 65(21): 9643 - 9650. [Abstract] [Full Text] [PDF] S. D. Westfall and M. K. Skinner Inhibition of phosphatidylinositol 3-kinase sensitizes ovarian cancer cells to carboplatin and allows adjunct chemotherapy treatment Mol. Cancer Ther., November 1, 2005; 4(11): 1764 - 1771. [Abstract] [Full Text] [PDF] P. Sujobert, V. Bardet, P. Cornillet-Lefebvre, J. S. Hayflick, N. Prie, F. Verdier, B. Vanhaesebroeck, O. Muller, F. Pesce, N. Ifrah, et al. 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Payrastre Antileukemic activity of rapamycin in acute myeloid leukemia Blood, March 15, 2005; 105(6): 2527 - 2534. [Abstract] [Full Text] [PDF] W. H. Mondesire, W. Jian, H. Zhang, J. Ensor, M.-C. Hung, G. B. Mills, and F. Meric-Bernstam Targeting Mammalian Target of Rapamycin Synergistically Enhances Chemotherapy-Induced Cytotoxicity in Breast Cancer Cells Clin. Cancer Res., October 15, 2004; 10(20): 7031 - 7042. [Abstract] [Full Text] [PDF] J. P. Dutcher Mammalian Target of Rapamycin Inhibition Clin. Cancer Res., September 15, 2004; 10(18): 6382S - 6387S. [Abstract] [Full Text] [PDF] D. G. Gilliland, C. T. Jordan, and C. A. Felix The Molecular Basis of Leukemia Hematology, January 1, 2004; 2004(1): 80 - 97. [Abstract] [Full Text] [PDF]

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