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SRC is a signaling mediator in FLT3-ITD-but not in FLT3-TKD-positive AML

Leischner, Hannes; Albers, Corinna; Grundler, Rebekka; Razumovskaya, Elena LU ; Spiekermann, Karsten; Bohlander, Stefan; Rönnstrand, Lars LU ; Goetze, Katharina; Peschel, Christian and Duyster, Justus (2012) In Blood 119(17). p.4026-4033
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.... (More)
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 sitespecific Abs, we found that both residues were significantly more strongly phosphorylated in FLT3-ITD compared with FLT3-TKD. SRC inhibition and knockdown 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. (Blood. 2012;119(17):4026-4033) (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
119
issue
17
pages
4026 - 4033
publisher
American Society of Hematology
external identifiers
  • wos:000305282900025
  • scopus:84860316784
ISSN
1528-0020
DOI
10.1182/blood-2011-07-365726
language
English
LU publication?
yes
id
83909a68-3b6c-4db7-b863-6285705bd34c (old id 2890884)
date added to LUP
2012-08-01 08:55:15
date last changed
2017-11-05 03:02:39
@article{83909a68-3b6c-4db7-b863-6285705bd34c,
  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 sitespecific Abs, we found that both residues were significantly more strongly phosphorylated in FLT3-ITD compared with FLT3-TKD. SRC inhibition and knockdown 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. (Blood. 2012;119(17):4026-4033)},
  author       = {Leischner, Hannes and Albers, Corinna and Grundler, Rebekka and Razumovskaya, Elena and Spiekermann, Karsten and Bohlander, Stefan and Rönnstrand, Lars and Goetze, Katharina and Peschel, Christian and Duyster, Justus},
  issn         = {1528-0020},
  language     = {eng},
  number       = {17},
  pages        = {4026--4033},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {SRC is a signaling mediator in FLT3-ITD-but not in FLT3-TKD-positive AML},
  url          = {http://dx.doi.org/10.1182/blood-2011-07-365726},
  volume       = {119},
  year         = {2012},
}