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 & 23 others Christopher Famulare, Minal Patel, Elisabeth M. 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

14 Citations (Scopus)

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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Myeloid Progenitor Cells
Myeloid Leukemia
RNA-Binding Proteins
Leukemia
Neoplastic Stem Cells
Gene Expression Profiling
Myeloid Cells
Proteomics
Small Interfering RNA
Genes
Stem Cells
Apoptosis
Messenger RNA

ASJC Scopus subject areas

  • Genetics

Cite this

Vu, L. P., Prieto, C., Amin, E. M., Chhangawala, S., Krivtsov, A., Calvo-Vidal, M. N., ... 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

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; Park, Sun Mi; Barlowe, Trevor S.; Taggart, James; Tivnan, Patrick; Deering, Raquel P.; Chu, Lisa P.; Kwon, Jeong Ah; Meydan, Cem; Perales-Paton, Javier; Arshi, Arora; Gönen, Mithat; Famulare, Christopher; Patel, Minal; Paietta, Elisabeth M.; Tallman, Martin S.; Lu, Yuheng; Glass, Jacob; Garret-Bakelman, Francine E.; Melnick, Ari; Levine, Ross; Al-Shahrour, Fatima; Järås, Marcus; Hacohen, Nir; Hwang, Alexia; Garippa, Ralph; Lengner, Christopher J.; Armstrong, Scott A.; Cerchietti, Leandro; Cowley, Glenn S.; Root, David; Doench, John; Leslie, Christina; Ebert, Benjamin L.; Kharas, Michael G.

In: Nature Genetics, Vol. 49, No. 6, 01.06.2017, p. 866-875.

Research output: Contribution to journalArticle

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, EM, 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
Vu LP, Prieto C, Amin EM, Chhangawala S, Krivtsov A, Calvo-Vidal MN et al. Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells. Nature Genetics. 2017 Jun 1;49(6):866-875. https://doi.org/10.1038/ng.3854
Vu, Ly P. ; Prieto, Camila ; Amin, Elianna M. ; Chhangawala, Sagar ; Krivtsov, Andrei ; Calvo-Vidal, M. Nieves ; Chou, Timothy ; Chow, Arthur ; Minuesa, Gerard ; Park, Sun Mi ; Barlowe, Trevor S. ; Taggart, James ; Tivnan, Patrick ; Deering, Raquel P. ; Chu, Lisa P. ; Kwon, Jeong Ah ; Meydan, Cem ; Perales-Paton, Javier ; Arshi, Arora ; Gönen, Mithat ; Famulare, Christopher ; Patel, Minal ; Paietta, Elisabeth M. ; Tallman, Martin S. ; Lu, Yuheng ; Glass, Jacob ; Garret-Bakelman, Francine E. ; Melnick, Ari ; Levine, Ross ; Al-Shahrour, Fatima ; Järås, Marcus ; Hacohen, Nir ; Hwang, Alexia ; Garippa, Ralph ; Lengner, Christopher J. ; Armstrong, Scott A. ; Cerchietti, Leandro ; Cowley, Glenn S. ; Root, David ; Doench, John ; Leslie, Christina ; Ebert, Benjamin L. ; Kharas, Michael G. / Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells. In: Nature Genetics. 2017 ; Vol. 49, No. 6. pp. 866-875.
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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.",
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AU - Vu, Ly P.

AU - Prieto, Camila

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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 M.

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

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