title: SYK is a critical regulator of FLT3 in acute myeloid leukemia.
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.
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors: Alexandre
authors: A
authors: Puissant
authors: Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors: Nina
authors: N
authors: Fenouille
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Bioinformatics Graduate Program, Boston University, Boston, MA 02215, USA.
authors: Gabriela
authors: G
authors: Alexe
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors: Yana
authors: Y
authors: Pikman
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors: Christopher F
authors: CF
authors: Bassil
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors: Swapnil
authors: S
authors: Mehta
authors: The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors: Jinyan
authors: J
authors: Du
authors: Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Medicon Village, 221 00 Lund, Sweden.
authors: Julhash U
authors: JU
authors: Kazi
authors: C3M/ INSERM U1065 Team Cell Death, Differentiation, Inflammation and Cancer, 06204 Nice, France.
authors: Frédéric
authors: F
authors: Luciano
authors: Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Medicon Village, 221 00 Lund, Sweden.
authors: Lars
authors: L
authors: Rönnstrand
authors: Pediatric Department, Columbia University Medical Center, New York, NY 10032, USA.
authors: Andrew L
authors: AL
authors: Kung
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors: Jon C
authors: JC
authors: Aster
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors: Ilene
authors: I
authors: Galinsky
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors: Richard M
authors: RM
authors: Stone
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors: Daniel J
authors: DJ
authors: DeAngelo
authors: Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors: Michael T
authors: MT
authors: Hemann
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: kimberly_stegmaier@dfci.harvard.edu.
authors: Kimberly
authors: K
authors: Stegmaier
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D000072377:Syk Kinase; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D005472:Fluorouracil