Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia. Syncrip was the most differentially required gene between normal and myeloid leukemia cells. SYNCRIP depletion increased apoptosis and differentiation while delaying leukemogenesis. Gene expression profiling of SYNCRIP-depleted cells demonstrated a loss of the MLL and HOXA9 leukemia stem cell program. SYNCRIP and MSI2 interact indirectly though shared mRNA targets. SYNCRIP maintains HOXA9 translation, and MSI2 or HOXA9 overexpression rescued the effects of SYNCRIP depletion. Altogether, our data identify SYNCRIP as a new RBP that controls the myeloid leukemia stem cell program. We propose that targeting these RBP complexes might provide a novel therapeutic strategy in leukemia.

Detaljer

Författare
  • Ly P. Vu
  • Camila Prieto
  • Elianna M. Amin
  • Sagar Chhangawala
  • Andrei Krivtsov
  • M. Nieves Calvo-Vidal
  • Timothy Chou
  • Arthur Chow
  • Gerard Minuesa
  • Sun Mi Park
  • Trevor S. Barlowe
  • James Taggart
  • Patrick Tivnan
  • Raquel P. Deering
  • Lisa P. Chu
  • Jeong Ah Kwon
  • Cem Meydan
  • Javier Perales-Paton
  • Arora Arshi
  • Mithat Gönen
  • Christopher Famulare
  • Minal Patel
  • Elisabeth Paietta
  • Martin S. Tallman
  • Yuheng Lu
  • Jacob Glass
  • Francine E. Garret-Bakelman
  • Ari Melnick
  • Ross L. Levine
  • Fatima Al-Shahrour
  • Nir Hacohen
  • Alexia Hwang
  • Ralph Garippa
  • Christopher J. Lengner
  • Scott A. Armstrong
  • Leandro Cerchietti
  • Glenn S. Cowley
  • David E. Root
  • John Doench
  • Christina Leslie
  • Benjamin L. Ebert
  • Michael G. Kharas
Enheter & grupper
Externa organisationer
  • Memorial Sloan-Kettering Cancer Center
  • Cornell University
  • Harvard Medical School
  • Weill Cornell Medical College
  • Brigham and Women's Hospital / Harvard Medical School
  • Whitehead Institute for Biomedical Research
  • Spanish National Cancer Research Center (CNIO)
  • Montefiore Medical Center
  • University of Virginia
  • University of Pennsylvania
  • Janssen Research & Development LLC
  • Broad Institute
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi
Originalspråkengelska
Sidor (från-till)866-875
Antal sidor10
TidskriftNature Genetics
Volym49
Utgivningsnummer6
StatusPublished - 2017 jun 1
PublikationskategoriForskning
Peer review utfördJa