Activation mechanisms of STAT5 by oncogenic Flt3-ITD.
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.
Choudhary
Chunaram
C
Department of Medicine, Interdisciplinary Center for Clinical Research, University of Münster, Münster, Germany.
Brandts
Christian
C
Schwable
Joachim
J
Tickenbrock
Lara
L
Sargin
Bülent
B
Ueker
Andrea
A
Böhmer
Frank-D
FD
Berdel
Wolfgang E
WE
Müller-Tidow
Carsten
C
Serve
Hubert
H
D000818:Animals; D002460:Cell Line; D053614:Janus Kinase 2; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053634:TYK2 Kinase; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D050799:STAT5 Transcription Factor; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse