MSI2相互作用蛋白的功能筛选确定了SYNCRIP在髓系白血病干细胞中的重要作用。
Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells.
作者信息
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, 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
机构信息
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.
Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, USA.
出版信息
Nat Genet. 2017 Jun;49(6):866-875. doi: 10.1038/ng.3854. Epub 2017 Apr 24.
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.
调控癌症干细胞的RNA结合蛋白（RBP）的特性仍不清楚。MSI2 RBP是癌症干细胞程序翻译的核心调节因子。通过对与MSI2相互作用的RBP网络进行蛋白质组学分析和功能性短发夹RNA（shRNA）筛选，我们鉴定出24个体内白血病所需的基因。Syncrip是正常细胞和髓系白血病细胞之间差异需求最大的基因。SYNCRIP缺失增加了细胞凋亡和分化，同时延缓了白血病的发生。对SYNCRIP缺失细胞的基因表达谱分析表明，MLL和HOXA9白血病干细胞程序缺失。SYNCRIP和MSI2通过共享的mRNA靶点间接相互作用。SYNCRIP维持HOXA9的翻译，MSI2或HOXA9的过表达挽救了SYNCRIP缺失的影响。总之，我们的数据确定SYNCRIP是一种控制髓系白血病干细胞程序的新RBP。我们提出，靶向这些RBP复合物可能为白血病提供一种新的治疗策略。
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