Back to Search
Start Over
SRC is a signaling mediator in FLT3-ITD- but not in FLT3-TKD-positive AML.
- Source :
-
Blood [Blood] 2012 Apr 26; Vol. 119 (17), pp. 4026-33. Date of Electronic Publication: 2012 Mar 12. - Publication Year :
- 2012
-
Abstract
- Mutations of Fms-like tyrosine kinase 3 (FLT3) are among the most frequently detected molecular abnormalities in AML patients. Internal tandem duplications (ITDs) are found in approximately 25% and point mutations within the second tyrosine kinase domain (TKD) in approximately 7% of AML patients. Patients carrying the FLT3-ITD but not the FLT3-TKD mutation have a significantly worse prognosis. Therefore, both FLT3 mutations seem to exert different biologic functions. FLT3-ITD but not FLT3-TKD has been shown to induce robust activation of the STAT5 signaling pathway. In the present study, we investigated the mechanisms leading to differential STAT5 activation and show that FLT3-ITD but not FLT3-TKD uses SRC to activate STAT5. Coimmunoprecipitation and pull-down experiments revealed an exclusive interaction between SRC but not other Src family kinases and FLT3-ITD, which is mediated by the SRC SH2 domain. We identified tyrosines 589 and 591 of FLT3-ITD to be essential for SRC binding and subsequent STAT5 activation. Using site-specific Abs, we found that both residues were significantly more strongly phosphorylated in FLT3-ITD compared with FLT3-TKD. SRC inhibition and knock-down blocked STAT5 activation and proliferation induced by FLT3-ITD but not by FLT3-TKD. We conclude that SRC might be a therapeutic target in FLT3-ITD(+) AML.
- Subjects :
- Animals
Blotting, Western
Cell Proliferation
Cells, Cultured
Flow Cytometry
Humans
Immunoprecipitation
Mice
Mice, Inbred C3H
NIH 3T3 Cells
Phosphorylation
RNA, Small Interfering genetics
STAT5 Transcription Factor metabolism
Signal Transduction
src Homology Domains
src-Family Kinases antagonists & inhibitors
src-Family Kinases genetics
Leukemia, Myeloid, Acute metabolism
Leukemia, Myeloid, Acute pathology
Protein-Tyrosine Kinases metabolism
Tandem Repeat Sequences genetics
fms-Like Tyrosine Kinase 3 metabolism
src-Family Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 119
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 22411868
- Full Text :
- https://doi.org/10.1182/blood-2011-07-365726