2. Academic Validation
  3. SYK is a critical regulator of FLT3 in acute myeloid leukemia

SYK is a critical regulator of FLT3 in acute myeloid leukemia

  • Cancer Cell. 2014 Feb 10;25(2):226-42. doi: 10.1016/j.ccr.2014.01.022.
Alexandre Puissant 1,  Nina Fenouille 2,  Gabriela Alexe 3,  Yana Pikman 1,  Christopher F Bassil 1,  Swapnil Mehta 1,  Jinyan Du 4,  Julhash U Kazi 5,  Frédéric Luciano 6,  Lars Rönnstrand 5,  Andrew L Kung 7,  Jon C Aster 8,  Ilene Galinsky 9,  Richard M Stone 9,  Daniel J DeAngelo 9,  Michael T Hemann 2,  Kimberly Stegmaier 10
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 2 Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 3 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.
  • 4 The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 5 Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Medicon Village, 221 00 Lund, Sweden.
  • 6 C3M/ INSERM U1065 Team Cell Death, Differentiation, Inflammation and Cancer, 06204 Nice, France.
  • 7 Pediatric Department, Columbia University Medical Center, New York, NY 10032, USA.
  • 8 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 10 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.
PMID: 24525236 DOI: 10.1016/j.ccr.2014.01.022
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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