| Literature DB >> 24525236 |
Alexandre Puissant1, Nina Fenouille2, Gabriela Alexe3, Yana Pikman1, Christopher F Bassil1, Swapnil Mehta1, Jinyan Du4, Julhash U Kazi5, Frédéric Luciano6, Lars Rönnstrand5, Andrew L Kung7, Jon C Aster8, Ilene Galinsky9, Richard M Stone9, Daniel J DeAngelo9, Michael T Hemann2, Kimberly Stegmaier10.
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.Entities:
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Year: 2014 PMID： 24525236 PMCID： PMC4106711 DOI： 10.1016/j.ccr.2014.01.022
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743