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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.

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NEOPLASIA

Brief Report

Activation mechanisms of STAT5 by oncogenic Flt3-ITD

Chunaram Choudhary1, Christian Brandts1, Joachim Schwable1, Lara Tickenbrock1, Bülent Sargin1, Andrea Ueker2, Frank-D. Böhmer2, Wolfgang E. Berdel1, Carsten Müller-Tidow1, and Hubert Serve1

1 Department of Medicine, Hematology/Oncology and the Interdisciplinary Center for Clinical Research, University of Münster, Germany; 2 Institute of Molecular Cell Biology, University of Jena, Germany

Mutations in the receptor tyrosine kinase Flt3 represent a very common genetic lesion in acute myeloid leukemia (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.


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