蛋白质精氨酸甲基转移酶5
癌症研究
RNA结合蛋白
生物
靶向治疗
细胞凋亡
细胞周期检查点
突变
细胞周期
分子生物学
甲基转移酶
基因
核糖核酸
遗传学
甲基化
癌症
作者
Tatiana Erazo,Chiara M. Evans,Daniel Zakheim,Karen L. Chu,Alice Yunsi Refermat,Zahra Asgari,Xuejing Yang,Mariana da Silva Ferreira,Sanjoy Mehta,Marco Russo,Andrea Knezevic,Xiping Zhang,Zhengming Chen,Myles Fennell,Ralph Garippa,Venkatraman Seshan,Elisa de Stanchina,Olena Barbash,Connie Lee Batlevi,Christina Leslie,Ari Melnick,Anas Younes,Michael G. Kharas
标识
DOI:10.1038/s41467-022-33137-8
摘要
To identify drivers of sensitivity and resistance to Protein Arginine Methyltransferase 5 (PRMT5) inhibition, we perform a genome-wide CRISPR/Cas9 screen. We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. TP53 deletion and TP53R248W mutation are biomarkers of resistance to GSK-591. PRMT5 expression correlates with MSI2 expression in lymphoma patients. MSI2 depletion and pharmacological inhibition using Ro 08-2750 (Ro) both synergize with GSK-591 to reduce cell growth. Ro reduces MSI2 binding to its global targets and dual treatment of Ro and PRMT5 inhibitors result in synergistic gene expression changes including cell cycle, P53 and MYC signatures. Dual MSI2 and PRMT5 inhibition further blocks c-MYC and BCL-2 translation. BCL-2 depletion or inhibition with venetoclax synergizes with a PRMT5 inhibitor by inducing reduced cell growth and apoptosis. Thus, we propose a therapeutic strategy in lymphoma that combines PRMT5 with MSI2 or BCL-2 inhibition.
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