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Nat Genet. 2017 Jun;49(6):866-875. doi: 10.1038/ng.3854. Epub 2017 Apr 24.

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

Author information

1
Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, and Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
2
Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, USA.
3
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
4
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
5
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Medicine, Division of Hematology/Oncology, Weill Cornell Medical College, New York, New York, USA.
7
Harvard Medical School, Boston, Massachusetts, USA.
8
Division of Hematology, Brigham and Woman's Hospital, Boston, Massachusetts, USA.
9
Whitehead Institute, Boston, Massachusetts, USA.
10
Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, USA.
11
Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre, Madrid, Spain.
12
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
13
Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
14
Department of Medicine, Montefiore Medical Center, Bronx, New York, USA.
15
Leukemia Service, Department of Medicine, Memorial Sloan Kettering Hospital, New York, New York, USA.
16
Department of Medicine and Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
17
Division of Hematology and Medical Oncology, Departments of Medicine and Pharmacology, Weill Cornell Medical College, Cornell University, New York, New York, USA.
18
Department of Clinical Genetics, Lund University, Lund, Sweden.
19
RNAi Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
20
Department of Animal Biology, Department of Cell and Developmental Biology, and Institute for Regenerative Medicine, Schools of Veterinary Medicine and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
21
Discovery Sciences, Janssen Research and Development, Spring House, Pennsylvania, USA.
22
Broad Institute, Boston, Massachusetts, USA.

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.

PMID:
28436985
PMCID:
PMC5508533
DOI:
10.1038/ng.3854
[Indexed for MEDLINE]
Free PMC Article

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