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 Gönen; Christopher 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

doi:10.1038/ng.3854

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^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

70 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 language	English (US)
Pages (from-to)	866-875
Number of pages	10
Journal	Nature Genetics
Volume	49
Issue number	6
DOIs	https://doi.org/10.1038/ng.3854
State	Published - Jun 1 2017

Funding

M.G.K. was supported by the US National Institutes of Health National Institute of Diabetes, Digestive and Kidney Diseases Career Development Award, NIDDK NIH R01-DK101989-01A1, NCI 1R01CA193842-01, Louis V. Gerstner Young Investigator Award, American Society of Hematology Junior Scholar Award, Kimmel Scholar Award, V-Scholar Award, Geoffrey Beene Award and Alex's Lemonade Stand A Award and the Starr Foundation (M.G.K. and L.C.). L.P.V. is supported by the Damon Runyon-Sohn Pediatric Cancer Fellowship Award, E.P. was supported by grants U24 CA114737 and U10 CA180827. C.J.L. was supported by an R01 grant from the National Cancer Institute (NIH) and a fellowship from the W.W. Smith Charitable Trust. The research was funded in part through NIH/NCI Cancer Support Core Grant P30 CA08748 to M.G.K. and R.G.

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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

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title = "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.",

author = "Vu, {Ly P.} and Camila Prieto and Amin, {Elianna M.} and Sagar Chhangawala and Andrei Krivtsov and Calvo-Vidal, {M. Nieves} and Timothy Chou and Arthur Chow and Gerard Minuesa and Park, {Sun Mi} and Barlowe, {Trevor S.} and James Taggart and Patrick Tivnan and Deering, {Raquel P.} and Chu, {Lisa P.} and Kwon, {Jeong Ah} and Cem Meydan and Javier Perales-Paton and Arora Arshi and Mithat G{\"o}nen and Christopher Famulare and Minal Patel and Elisabeth Paietta and Tallman, {Martin S.} and Yuheng Lu and Jacob Glass and Garret-Bakelman, {Francine E.} and Ari Melnick and Ross Levine and Fatima Al-Shahrour and Marcus J{\"a}r{\aa}s and Nir Hacohen and Alexia Hwang and Ralph Garippa and Lengner, {Christopher J.} and Armstrong, {Scott A.} and Leandro Cerchietti and Cowley, {Glenn S.} and David Root and John Doench and Christina Leslie and Ebert, {Benjamin L.} and Kharas, {Michael G.}",

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Vu, LP, Prieto, C, Amin, EM, Chhangawala, S, Krivtsov, A, Calvo-Vidal, MN, Chou, T, Chow, A, Minuesa, G, Park, SM, Barlowe, TS, Taggart, J, Tivnan, P, Deering, RP, Chu, LP, Kwon, JA, Meydan, C, Perales-Paton, J, Arshi, A, Gönen, M, Famulare, C, Patel, M, Paietta, E, Tallman, MS, Lu, Y, Glass, J, Garret-Bakelman, FE, Melnick, A, Levine, R, Al-Shahrour, F, Järås, M, Hacohen, N, Hwang, A, Garippa, R, Lengner, CJ, Armstrong, SA, Cerchietti, L, Cowley, GS, Root, D, Doench, J, Leslie, C, Ebert, BL & Kharas, MG 2017, 'Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells', Nature Genetics, vol. 49, no. 6, pp. 866-875. https://doi.org/10.1038/ng.3854

TY - JOUR

T1 - Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells

AU - Vu, Ly P.

AU - Prieto, Camila

AU - Amin, Elianna M.

AU - Chhangawala, Sagar

AU - Krivtsov, Andrei

AU - Calvo-Vidal, M. Nieves

AU - Chou, Timothy

AU - Chow, Arthur

AU - Minuesa, Gerard

AU - Park, Sun Mi

AU - Barlowe, Trevor S.

AU - Taggart, James

AU - Tivnan, Patrick

AU - Deering, Raquel P.

AU - Chu, Lisa P.

AU - Kwon, Jeong Ah

AU - Meydan, Cem

AU - Perales-Paton, Javier

AU - Arshi, Arora

AU - Gönen, Mithat

AU - Famulare, Christopher

AU - Patel, Minal

AU - Paietta, Elisabeth

AU - Tallman, Martin S.

AU - Lu, Yuheng

AU - Glass, Jacob

AU - Garret-Bakelman, Francine E.

AU - Melnick, Ari

AU - Levine, Ross

AU - Al-Shahrour, Fatima

AU - Järås, Marcus

AU - Hacohen, Nir

AU - Hwang, Alexia

AU - Garippa, Ralph

AU - Lengner, Christopher J.

AU - Armstrong, Scott A.

AU - Cerchietti, Leandro

AU - Cowley, Glenn S.

AU - Root, David

AU - Doench, John

AU - Leslie, Christina

AU - Ebert, Benjamin L.

AU - Kharas, Michael G.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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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C2 - 28436985

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JF - Nature Genetics

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ER -

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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