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Prepublished online as a Blood First Edition Paper on March 27, 2003; DOI 10.1182/blood-2002-06-1890. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-06-1890v1 102/2/630    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 Faderl, S. Articles by Estrov, Z. Search for Related Content PubMed PubMed Citation Articles by Faderl, S. Articles by Estrov, Z. Related Collections Apoptosis Signal Transduction Hematopoiesis and Stem Cells Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 July 2003, Vol. 102, No. 2, pp. 630-637 NEOPLASIA Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces antiapoptotic and proapoptotic signals in acute myeloid leukemia Stefan Faderl, David Harris, Quin Van, Hagop M. Kantarjian, Moshe Talpaz, and Zeev Estrov From the Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston; and the Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston High levels of cytokines are associated with a poor prognosis in acute myeloid leukemia (AML). However, cytokines may induce, on one hand, survival factor expression and cell proliferation and, on the other hand, expression of inhibitory signals such as up-regulation of suppressors of cytokine signaling (SOCS) and induce apoptotic cell death. Because blasts from patients with AML express high procaspase protein levels, we asked whether granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances procaspase protein production in AML cells. In the GM-CSF–responsive OCIM2 AML cell line, GM-CSF induced signal transducer and activator of transcription 5 (Stat 5) phosphorylation, up-regulated cyclin D2, and stimulated cell cycle progression. Concurrently, GM-CSF stimulated expression of SOCS-2 and -3 and of procaspases 2 and 3 and induced caspase 3 activation, poly(ADP[adenosine 5'-diphosphate]-ribose) polymerase (PARP) cleavage, and apoptotic cell death. The Janus kinase (Jak)–Stat inhibitor AG490 abrogated GM-CSF–induced expression of procaspase 3 and activation of caspase 3. Under the same conditions GM-CSF up-regulated production of BAX as well as Bcl-2, Bcl-XL, survivin, and XIAP. GM-CSF also increased procaspase 3 protein levels in OCI/AML3 and Mo7e cells, suggesting that this phenomenon is not restricted to a single leukemia cell line. Our data suggest that GM-CSF exerts a dual effect: it stimulates cell division but contemporaneously up-regulates Jak-Stat–dependent proapoptotic proteins. Up-regulation of procaspase levels in AML is thus a beacon for an ongoing growth-stimulatory signal. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Verstovsek, T. Manshouri, A. Quintas-Cardama, D. Harris, J. Cortes, F. J. Giles, H. Kantarjian, W. Priebe, and Z. Estrov WP1066, a Novel JAK2 Inhibitor, Suppresses Proliferation and Induces Apoptosis in Erythroid Human Cells Carrying the JAK2 V617F Mutation Clin. Cancer Res., February 1, 2008; 14(3): 788 - 796. [Abstract] [Full Text] [PDF] B. Gyurkocza, J. Plescia, C. M. Raskett, D. S. Garlick, P. A. Lowry, B. Z. Carter, M. Andreeff, M. Meli, G. Colombo, and D. C. Altieri Antileukemic activity of shepherdin and molecular diversity of hsp90 inhibitors. J Natl Cancer Inst, August 2, 2006; 98(15): 1068 - 1077. [Abstract] [Full Text] [PDF] C. H. M. Jamieson, J. Gotlib, J. A. Durocher, M. P. Chao, M. R. Mariappan, M. Lay, C. Jones, J. L. Zehnder, S. L. Lilleberg, and I. L. Weissman The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation PNAS, April 18, 2006; 103(16): 6224 - 6229. [Abstract] [Full Text] [PDF]

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