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


Authors: 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.; Gönen, M.; Famulare, C.; Patel, M.; Paietta, E.; Tallman, M. S.; Lu, Y.; Glass, J.; Garret-Bakelman, F. E.; Melnick, A.; Levine, R.; Al-Shahrour, F.; Järås, M.; Hacohen, N.; Hwang, A.; Garippa, R.; Lengner, C. J.; Armstrong, S. A.; Cerchietti, L.; Cowley, G. S.; Root, D.; Doench, J.; Leslie, C.; Ebert, B. L.; Kharas, M. G.
Article 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. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
Keywords: controlled study; protein expression; gene translocation; human cell; nonhuman; animal cell; animal tissue; gene; cell survival; apoptosis; gene expression; gene expression profiling; in vivo study; cell differentiation; in vitro study; proteomics; messenger rna; nucleic acid analysis; gene interaction; leukemogenesis; cancer stem cell; hematopoiesis; fetus; short hairpin rna; rna binding; myeloid leukemia; transcription factor hoxa9; mixed lineage leukemia protein; human; priority journal; article; myeloid leukemia cell line; crispr cas system; msi2 gene; syncrip gene
Journal Title: Nature Genetics
Volume: 49
Issue: 6
ISSN: 1061-4036
Publisher: Nature Publishing Group  
Date Published: 2017-06-01
Start Page: 866
End Page: 875
Language: English
DOI: 10.1038/ng.3854
PROVIDER: scopus
PUBMED: 28436985
PMCID: PMC5508533
DOI/URL:
Notes: Arshi Arora's first and last names are reversed on the original publication -- Article -- Export Date: 3 July 2017 -- Source: Scopus
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MSK Authors
  1. Mithat Gonen
    734 Gonen
  2. Martin Stuart Tallman
    454 Tallman
  3. Ross Levine
    504 Levine
  4. Christina Leslie
    117 Leslie
  5. Ly P Vu
    31 Vu
  6. Minal A Patel
    40 Patel
  7. Patrick Edward Tivnan
    10 Tivnan
  8. Michael Kharas
    53 Kharas
  9. Sun Mi Park
    15 Park
  10. Arshi Arora
    21 Arora
  11. Scott Allen Armstrong
    108 Armstrong
  12. Ralph James Garippa
    16 Garippa
  13. Yuheng Lu
    12 Lu
  14. Trevor Stephen Barlowe
    11 Barlowe
  15. James Christopher Taggart
    12 Taggart
  16. Jacob Lowell Glass
    19 Glass
  17. Alexia   Hwang
    3 Hwang
  18. Arthur W Chow
    13 Chow
  19. Camila Prieto
    5 Prieto
  20. Timothy Chou
    11 Chou