SRC is a signaling mediator in FLT3-ITD-but not in FLT3-TKD-positive AML
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2890884
- author
- Leischner, Hannes ; Albers, Corinna ; Grundler, Rebekka ; Razumovskaya, Elena LU ; Spiekermann, Karsten ; Bohlander, Stefan ; Rönnstrand, Lars LU ; Goetze, Katharina ; Peschel, Christian and Duyster, Justus
- organization
- publishing date
- 2012
- 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
- pmid:22411868
- ISSN
- 1528-0020
- DOI
- 10.1182/blood-2011-07-365726
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)
- id
- 83909a68-3b6c-4db7-b863-6285705bd34c (old id 2890884)
- date added to LUP
- 2016-04-01 09:56:07
- date last changed
- 2022-03-19 07:47:34
@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}}, doi = {{10.1182/blood-2011-07-365726}}, volume = {{119}}, year = {{2012}}, }