SYK is a critical regulator of FLT3 in acute myeloid leukemia.

Cancer Cell
Authors
Keywords
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.

Year of Publication
2014
Journal
Cancer Cell
Volume
25
Issue
2
Pages
226-42
Date Published
2014 Feb 10
ISSN
1878-3686
URL
DOI
10.1016/j.ccr.2014.01.022
PubMed ID
24525236
PubMed Central ID
PMC4106711
Links
Grant list
R01 CA140292 / CA / NCI NIH HHS / United States