SYK is a critical regulator of FLT3 in acute myeloid leukemia

Alexandre Puissant; Nina Fenouille; Gabriela Alexe; Yana Pikman; Christopher F Bassil; Swapnil Mehta; Jinyan Du; Julhash U Kazi; Frédéric Luciano; Lars Rönnstrand; Andrew L Kung; Jon C Aster; Ilene Galinsky; Richard M Stone; Daniel J DeAngelo; Michael T Hemann; Kimberly Stegmaier

doi:10.1016/j.ccr.2014.01.022

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.

Authors

Alexandre Puissant¹, Nina Fenouille², Gabriela Alexe³, Yana Pikman¹, Christopher F Bassil¹, Swapnil Mehta¹, Jinyan Du⁴, Julhash U Kazi⁵, Frédéric Luciano⁶, Lars Rönnstrand⁵, Andrew L Kung⁷, Jon C Aster⁸, Ilene Galinsky⁹, Richard M Stone⁹, Daniel J DeAngelo⁹, Michael T Hemann², Kimberly Stegmaier¹⁰

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antimetabolites, Antineoplastic / pharmacology
Apoptosis
Blotting, Western
Cell Proliferation
Cell Transformation, Neoplastic*
Cells, Cultured
Drug Resistance, Neoplasm*
Fluorouracil / pharmacology
Humans
Immunoenzyme Techniques
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / mortality
Leukemia, Myeloid, Acute / pathology*
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*
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Survival Rate
Syk Kinase
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
fms-Like Tyrosine Kinase 3 / genetics*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Antimetabolites, Antineoplastic
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
RNA, Messenger
FLT3 protein, human
Protein-Tyrosine Kinases
fms-Like Tyrosine Kinase 3
SYK protein, human
Syk Kinase
Syk protein, mouse
Fluorouracil

Associated data

GEO/GSE54065

Grants and funding

R01 CA140292/CA/NCI NIH HHS/United States