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.
