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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Gene Expression Omnibus
We would like to thank S. Nimer and N. Rosen for their critical advice and helpful suggestions. We would also like to thank A. Viale and the MSKCC sequencing core for all their support. We would like to thank the Lowe laboratory (Memorial Sloan Kettering Cancer Center) for their generous gift of the RN2 cells26 and the CRISPR–Cas9 constructs. We would like to thank Y. Neelamraju for technical support. 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.
Integrated supplementary information
Mass spectrometry list of MSI2 protein interactions.
Top 1,000 targets bound by MSI1 in the intestine.
List of gene sets used that are hematopoietic and MSI related.
Prioritization matrix gene list for pool 1a.
Prioritization matrix gene list for pool 1b.
Prioritization matrix gene list for pool 2.
Prioritization matrix for pool 3.
List of genes included in the in vivo shRNA screen associated with the MSI2 interactome.
Raw normalized read counts of all target sequences in the in vivo shRNA screen.
List of hits from the in vivo MSI2 interactome shRNA screen.
PCR primers for Syncrip CR-KO genotyping.
List of differentially expressed genes in Syncrip-shRNA leukemia cells with log2 (fold change) >1.5.
Ranked list of all genes expressed in Syncrip-shRNA leukemia cells with log2 (fold change).
GSEA analysis of enrichment for pathways that are negatively regulated by SYNCRIP.
GSEA analysis of enrichment for pathways that are positively regulated by SYNCRIP.
List of additional GSEA analysis for stem cell–associated pathways.
Information on primary AML samples from patients used in Figure 7f.