小柯机器人

武汉大学Haojian Zhang团队近期取得重要工作进展，他们通过解码m⁶A RNA甲基化组明确PRMT6调节的脂质转运促进AML干细胞的维持。相关研究结果2022年12月26日在线发表于《细胞—干细胞》杂志上。

据介绍，N6甲基腺苷（m⁶A）是哺乳动物mRNA的一种常见化学修饰，在各种生物学过程中表现出较高的动态性。然而，m⁶A RNA甲基化组在白血病发生过程中的动力学仍然未知。

研究人员描绘了急性髓系白血病（AML）发展过程中的综合m⁶A概况，并确定PRMT6是维持AML干细胞的关键因子。研究人员观察到在白血病发生过程中m⁶A甲基化组的明显变化，并发现精氨酸甲基转移酶PRMT6和m⁶A阅读器IGF2BP2蛋白维持人和小鼠白血病干细胞（LSC）的功能。PRMT6的基因缺失或药理抑制会损害AML的发育和LSC的功能。在机制上，IGF2BP2通过m⁶A介导的方式稳定PRMT6 mRNA，催化H3R2me2a并抑制脂质转运蛋白MFSD2A的表达。PRMT6缺失上调MFSD2A的表达，增加二十二碳六烯酸水平并损害LSC的维持。

总之，这一发现揭示了PRMT6-MFSD2A信号轴在AML发生过程中的关键作用，并为靶向LSC的治疗提供了策略。

附：英文原文

Title: Decoding m6A RNA methylome identifies PRMT6-regulated lipid transport promoting AML stem cell maintenance

Author: Ying Cheng, Zhuying Gao, Tiantian Zhang, Yuhua Wang, Xueqin Xie, Guoqiang Han, Yashu Li, Rong Yin, Yilin Chen, Peipei Wang, Jin Hu, Tong Zhang, Chengli Guo, Jihua Chai, Jing Wang, Manman Cui, Kexin Gao, Weidong Liu, Shuxin Yao, Pengbo Lu, Ziyan Cao, Yanbing Zheng, Jiwei Chang, Zheming Liu, Qibin Song, Weiming Li, Fuling Zhou, Haojian Zhang

Issue&Volume: 2022-12-26

Abstract: N6-methyladenosine (m6A) is a common chemical modification for mammalian mRNA and exhibits high dynamicsin various biological processes. However, dynamics of m6A RNA methylome during leukemogenesis remains unknown. Here, we delineate a comprehensivem6A landscape during acute myeloid leukemia (AML) development and identify PRMT6 asa key for maintaining AML stem cells. We observe an obvious change in m6A methylome during leukemogenesis and find that protein arginine methyltransferasePRMT6 and m6A reader IGF2BP2 maintain the function of human and murine leukemia stem cells (LSCs).Genetic deletion or pharmacological inhibition of PRMT6 damages AML development andLSC function. Mechanistically, IGF2BP2 stabilizes PRMT6 mRNA via m6A-mediated manner, which catalyzes H3R2me2a and suppresses lipid transporter MFSD2Aexpression. PRMT6 loss upregulates MFSD2A expression that increases docosahexaenoicacid levels and impairs LSC maintenance. Collectively, our findings reveal a criticalrole of PRMT6-MFSD2A signaling axis in AML development and provide a therapeutic strategyfor targeting LSCs.

DOI: 10.1016/j.stem.2022.12.003

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00487-8

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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