SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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
Enheter & grupper
Externa organisationer
  • Harvard Medical School
  • Massachusetts Institute of Technology
  • Boston University
  • Mediterranean Centre for Molecular Medicine
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Sidor (från-till)226-242
TidskriftCancer Cell
Volym25
Utgivningsnummer2
StatusPublished - 2014
PublikationskategoriForskning
Peer review utfördJa