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

Vu, Ly P.; Prieto, Camila; Amin, Elianna M.; Chhangawala, Sagar; Krivtsov, Andrei; Calvo-Vidal, M. Nieves; Chou, Timothy; Chow, Arthur; Minuesa, Gerard and Park, Sun Mi, et al. (2017) In Nature Genetics 49(6). p.866-875
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... (More)

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.

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@article{ddd9e50b-b14c-4d70-bd3a-b51784573900,
  abstract     = {<p>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.</p>},
  author       = {Vu, Ly P. and Prieto, Camila and Amin, Elianna M. and Chhangawala, Sagar and Krivtsov, Andrei and Calvo-Vidal, M. Nieves and Chou, Timothy and Chow, Arthur and Minuesa, Gerard and Park, Sun Mi and Barlowe, Trevor S. and Taggart, James and Tivnan, Patrick and Deering, Raquel P. and Chu, Lisa P. and Kwon, Jeong Ah and Meydan, Cem and Perales-Paton, Javier and Arshi, Arora and Gönen, Mithat and Famulare, Christopher and Patel, Minal and Paietta, Elisabeth and Tallman, Martin S. and Lu, Yuheng and Glass, Jacob and Garret-Bakelman, Francine E. and Melnick, Ari and Levine, Ross L. and Al-Shahrour, Fatima and Järås, Marcus and Hacohen, Nir and Hwang, Alexia and Garippa, Ralph and Lengner, Christopher J. and Armstrong, Scott A. and Cerchietti, Leandro and Cowley, Glenn S. and Root, David E. and Doench, John and Leslie, Christina and Ebert, Benjamin L. and Kharas, Michael G.},
  issn         = {1061-4036},
  language     = {eng},
  month        = {06},
  number       = {6},
  pages        = {866--875},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells},
  url          = {http://dx.doi.org/10.1038/ng.3854},
  volume       = {49},
  year         = {2017},
}