Activation mechanisms of STAT5 by oncogenic Flt3-ITD
- 1 July 2007
- journal article
- Published by American Society of Hematology in Blood
- Vol. 110 (1) , 370-374
- https://doi.org/10.1182/blood-2006-05-024018
Abstract
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.Keywords
This publication has 25 references indexed in Scilit:
- Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITDBlood, 2006
- Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformationBlood, 2006
- STAT5-induced self-renewal and impaired myelopoiesis of human hematopoietic stem/progenitor cells involves down-modulation of C/EBPαBlood, 2006
- AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutationsBlood, 2005
- FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation modelBlood, 2005
- Enforced expression of an Flt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesisBlood, 2005
- Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutationsBlood, 2003
- Signal transducer and activator of transcription proteins in leukemiasBlood, 2003
- Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domainOncogene, 2002
- Src family kinases are required for integrin but not PDGFR signal transductionThe EMBO Journal, 1999