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


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.

SUBMITTER: Vu LP 

PROVIDER: S-EPMC5508533 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Vu Ly P LP   Prieto Camila C   Amin Elianna M EM   Chhangawala Sagar S   Krivtsov Andrei A   Calvo-Vidal M Nieves MN   Chou Timothy T   Chow Arthur A   Minuesa Gerard G   Park Sun Mi SM   Barlowe Trevor S TS   Taggart James J   Tivnan Patrick P   Deering Raquel P RP   Chu Lisa P LP   Kwon Jeong-Ah JA   Meydan Cem C   Perales-Paton Javier J   Arshi Arora A   Gönen Mithat M   Famulare Christopher C   Patel Minal M   Paietta Elisabeth E   Tallman Martin S MS   Lu Yuheng Y   Glass Jacob J   Garret-Bakelman Francine E FE   Melnick Ari A   Levine Ross R   Al-Shahrour Fatima F   Järås Marcus M   Hacohen Nir N   Hwang Alexia A   Garippa Ralph R   Lengner Christopher J CJ   Armstrong Scott A SA   Cerchietti Leandro L   Cowley Glenn S GS   Root David D   Doench John J   Leslie Christina C   Ebert Benjamin L BL   Kharas Michael G MG  

Nature genetics 20170424 6


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 delay  ...[more]

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