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SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia

Author(s)
Puissant, Alexandre; Alexe, Gabriela; Pikman, Yana; Bassil, Christopher F.; Mehta, Swapnil; Du, Jinyan; Kazi, Julhash U.; Luciano, Frédéric; Rönnstrand, Lars; Kung, Andrew L.; Aster, Jon C.; Galinsky, Ilene; Stone, Richard M.; DeAngelo, Daniel J.; Stegmaier, Kimberly; Fenouille, Nina; Hemann, Michael; ... Show more Show less
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Abstract
Cooperative dependencies between mutant oncoproteins and wild-type proteins are critical in cancer pathogenesis and therapy resistance. Although spleen tyrosine kinase (SYK) has been implicated in hematologic malignancies, it is rarely mutated. We used kinase activity profiling to identify collaborators of SYK in acute myeloid leukemia (AML) and determined that FMS-like tyrosine kinase 3 (FLT3) is transactivated by SYK via direct binding. Highly activated SYK is predominantly found in FLT3-ITD positive AML and cooperates with FLT3-ITD to activate MYC transcriptional programs. FLT3-ITD AML cells are more vulnerable to SYK suppression than FLT3 wild-type counterparts. In a FLT3-ITD in vivo model, SYK is indispensable for myeloproliferative disease (MPD) development, and SYK overexpression promotes overt transformation to AML and resistance to FLT3-ITD-targeted therapy.
Date issued
2014-02
URI
http://hdl.handle.net/1721.1/110404
Department
Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MIT
Journal
Cancer Cell
Publisher
Elsevier
Citation
Puissant, Alexandre, Nina Fenouille, Gabriela Alexe, Yana Pikman, Christopher F. Bassil, Swapnil Mehta, Jinyan Du, et al. “SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia.” Cancer Cell 25, no. 2 (February 2014): 226–242.
Version: Author's final manuscript
ISSN
1535-6108

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