SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia

• Published in: Cancer cell Vol. 25; no. 2; pp. 226 - 242
• Main Authors: Puissant, Alexandre, Fenouille, Nina, 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., Hemann, Michael T., Stegmaier, Kimberly
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.02.2014
• Subjects: Animals; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Blotting, Western; Cancer and Oncology; Cancer och onkologi; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Clinical Medicine; Drug Resistance, Neoplasm; Fluorouracil - pharmacology; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Humans; Immunoenzyme Techniques; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Klinisk medicin; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Medical and Health Sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred BALB C; Mutation - genetics; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Survival Rate; Syk Kinase
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccr.2014.01.022

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. •SYK binds and hyperactivates WT and mutant FLT3 receptors•In vivo, SYK is required for FLT3-ITD-induced MPD and promotes progression to AML•FLT3-ITD AML is more vulnerable to SYK suppression than FLT3 wild-type AML•Highly activated SYK can promote resistance to FLT3-ITD-targeted inhibitors Puissant et al. report that SYK and FLT3 cooperate in acute myeloid leukemia (AML) and that highly activated SYK mediates therapeutic resistance to FLT3 inhibitors. The authors make the clinically important finding that FLT3-ITD-driven AMLs are hypersensitive to SYK suppression.