SYK is a Critical Regulator of FLT3 in Acute Myeloid Leukemia

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2014 Feb 15

PMID 24525236

Citations 82

Authors

Alexandre Puissant

Nina Fenouille

Gabriela Alexe

Yana Pikman

Christopher F Bassil

Swapnil Mehta

Jinyan Du

Julhash U Kazi

Frederic Luciano

Lars Ronnstrand

Andrew L Kung

Jon C Aster

Ilene Galinsky

Richard M Stone

Daniel J DeAngelo

Michael T Hemann

Kimberly Stegmaier

Affiliations

Soon will be listed here.

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.

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