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

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 GönenChristopher Famulare, Minal Patel, Elisabeth Paietta, Martin S. Tallman, Yuheng Lu, Jacob Glass, Francine E. Garret-Bakelman, Ari Melnick, Ross Levine, Fatima Al-Shahrour, Marcus Järås, Nir Hacohen, Alexia Hwang, Ralph Garippa, Christopher J. Lengner, Scott A. Armstrong, Leandro Cerchietti, Glenn S. Cowley, David Root, John Doench, Christina Leslie, Benjamin L. Ebert, Michael G. Kharas

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)866-875
Number of pages10
JournalNature Genetics
Volume49
Issue number6
DOIs
StatePublished - Jun 1 2017

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ASJC Scopus subject areas

  • Genetics

Cite this

Vu, L. P., Prieto, C., Amin, E. M., Chhangawala, S., Krivtsov, A., Calvo-Vidal, M. N., Chou, T., Chow, A., Minuesa, G., Park, S. M., Barlowe, T. S., Taggart, J., Tivnan, P., Deering, R. P., Chu, L. P., Kwon, J. A., Meydan, C., Perales-Paton, J., Arshi, A., ... Kharas, M. G. (2017). Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells. Nature Genetics, 49(6), 866-875. https://doi.org/10.1038/ng.3854