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Blood, 1 July 2007, Vol. 110, No. 1, pp. 370-374. Prepublished online as a Blood First Edition Paper on March 13, 2007; DOI 10.1182/blood-2006-05-024018. This Article Full Text (PDF) Supplemental Methods All Versions of this Article: blood-2006-05-024018v1 110/1/370    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 Choudhary, C. Articles by Serve, H. Search for Related Content PubMed PubMed Citation Articles by Choudhary, C. Articles by Serve, H. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 22, 2006 Accepted January 4, 2007 Activation mechanisms of STAT5 by oncogenic Flt3-ITD Chunaram Choudhary, Christian Brandts, Joachim Schwable, Lara Tickenbrock, Bulent Sargin, Andrea Ueker, Frank-D. Bohmer, Wolfgang E. Berdel, Carsten Muller-Tidow, and Hubert Serve* Dept of Medicine, Hematology/Oncology, & the Interdisciplinary Center for Clinical Research, University of Munster, Munster, Germany Institute of Molecular Cell Biology, University of Jena, Jena, Germany * Corresponding author; email: serve{at}uni-muenster.de. Mutations in the receptor tyrosine kinase Flt3 represent a very common genetic lesion in AML. Internal tandem duplication (ITD) mutations clustered in the juxtamembrane domain are the most frequent and best characterized mutations found in Flt3. Oncogenic activation of Flt3 by ITD mutations is known to activate aberrant signaling including activation of STAT5 and repression of myeloid transcription factors Pu.1 and c/EBP-alpha. However, the mechanisms of STAT5 activation by Flt3-ITD remain unclear. Using small molecule inhibitors and cell lines deficient for Src family kinases or Jak2 or Tyk2, here we show that Flt3-ITD induced STAT5 activation is independent of Src or Jak kinases. Also, overexpression of SOCS1, an inhibitor of Jak kinases, inhibited IL-3 but not Flt3-ITD mediated STAT5 activation. Furthermore, in-vitro kinase assays revealed that STAT5 is a direct target of Flt3. Taken together, our data provide the mechanistic basis of STAT5 activation by Flt3-ITD. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. R. Bandi, C. Brandts, M. Rensinghoff, R. Grundler, L. Tickenbrock, G. Kohler, J. Duyster, W. E. Berdel, C. Muller-Tidow, H. Serve, et al. E3 ligase-defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease Blood, November 5, 2009; 114(19): 4197 - 4208. [Abstract] [Full Text] [PDF] M. Benekli, H. Baumann, and M. Wetzler Targeting Signal Transducer and Activator of Transcription Signaling Pathway in Leukemias J. Clin. Oncol., September 10, 2009; 27(26): 4422 - 4432. [Abstract] [Full Text] [PDF] K. W. Pratz, J. Cortes, G. J. Roboz, N. Rao, O. Arowojolu, A. Stine, Y. Shiotsu, A. Shudo, S. Akinaga, D. Small, et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response Blood, April 23, 2009; 113(17): 3938 - 3946. [Abstract] [Full Text] [PDF] M. Merad and M. G. Manz Dendritic cell homeostasis Blood, April 9, 2009; 113(15): 3418 - 3427. [Abstract] [Full Text] [PDF] D. Schmidt-Arras, S.-A. Bohmer, S. Koch, J. P. Muller, L. Blei, H. Cornils, R. Bauer, S. Korasikha, C. Thiede, and F.-D. Bohmer Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality Blood, April 9, 2009; 113(15): 3568 - 3576. [Abstract] [Full Text] [PDF]

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