TitleFunctional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells.
Publication TypeJournal Article
Year of Publication2017
AuthorsVu, Ly P., Prieto Camila, Amin Elianna M., Chhangawala Sagar, Krivtsov Andrei, M Calvo-Vidal 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, 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., and Kharas Michael G.
JournalNat Genet
Date Published2017 Jun
KeywordsAnimals, Cell Survival, Female, Gene Expression Regulation, Leukemic, Hematopoiesis, Heterogeneous-Nuclear Ribonucleoproteins, Homeodomain Proteins, Humans, Leukemia, Biphenotypic, Acute, Leukemia, Myeloid, Mice, Inbred C57BL, Mice, Knockout, Myeloid Progenitor Cells, RNA, Small Interfering, RNA-Binding Proteins, Xenograft Model Antitumor Assays

<p>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.</p>

Alternate JournalNat Genet
PubMed ID28436985
PubMed Central IDPMC5508533
Grant ListP30 CA015704 / CA / NCI NIH HHS / United States
U24 CA196172 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA193842 / CA / NCI NIH HHS / United States
U24 CA114737 / CA / NCI NIH HHS / United States
U10 CA180827 / CA / NCI NIH HHS / United States
R01 DK101989 / DK / NIDDK NIH HHS / United States
K01 DK084261 / DK / NIDDK NIH HHS / United States
R01 HL135564 / HL / NHLBI NIH HHS / United States