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Cancer Cell DOI:10.1016/j.ccr.2014.01.022

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

Publication TypeJournal Article
Year of Publication2014
AuthorsPuissant, A, Fenouille, N, Alexe, G, Pikman, Y, Bassil, CF, Mehta, S, Du, J, Kazi, JU, Luciano, F, Rönnstrand, L, Kung, AL, Aster, JC, Galinsky, I, Stone, RM, DeAngelo, DJ, Hemann, MT, Stegmaier, K
JournalCancer Cell
Volume25
Issue2
Pages226-42
Date Published2014 Feb 10
ISSN1878-3686
KeywordsAnimals, Antimetabolites, Antineoplastic, Apoptosis, Blotting, Western, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Drug Resistance, Neoplasm, Fluorouracil, fms-Like Tyrosine Kinase 3, Humans, Immunoenzyme Techniques, Intracellular Signaling Peptides and Proteins, Leukemia, Myeloid, Acute, Mice, Mice, Inbred BALB C, Mutation, Phosphorylation, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Survival Rate, Syk Kinase
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S1535-6108(14)00038-5
DOI10.1016/j.ccr.2014.01.022
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24525236?dopt=Abstract

Alternate JournalCancer Cell
PubMed ID24525236
PubMed Central IDPMC4106711
Grant ListR01 CA140292 / CA / NCI NIH HHS / United States