Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [IGF2BP2 RNA-seq]. Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [IGF2BP2 RNA-seq]

Our data reveal that RNA m6A displays a sharp transition during leukemogenesis and involves in acquiring stem cell properties of leukemia stem cells (LSCs). We find that m6A reader IGF2BP2 and protein arginine methyltransferase PRMT6 play key roles in the acquisition of LSCs properties. Genetical deletion and pharmacological inhibition of PRMT6 delayed AML development. Mechanistically, IGF2BP2 regulates PRMT6 expression by stabilizing its mRNA in an m6A-dependent manner. PRMT6 further suppresses the expression of lipid transporter MFSD2A by establishing inactive H3R2me2a in its promoter region. Loss of PRMT6 and IGF2BP2 upregulates the expression of MFSD2A that increases the uptake of docosahexaenoic acid. Collectively, our findings uncover a critical role of IGF2BP2-PRMT6-MFSD2A signaling axis in AML development, and provide a promising therapeutic strategy for targeting LSCs. Overall design: RNAseq of AML leukemia cell line (Molm13).

本研究数据显示，RNA N6-甲基腺嘌呤（RNA m6A）在白血病发生过程中存在剧烈的动态转变，并参与白血病干细胞（LSCs）干细胞特性的获取。我们发现，m6A阅读器胰岛素样生长因子2 mRNA结合蛋白2（IGF2BP2）以及蛋白质精氨酸甲基转移酶6（PRMT6）在白血病干细胞特性的获取中发挥关键作用。对PRMT6进行基因敲除与药理学抑制均可延缓急性髓系白血病（AML）的病程进展。机制层面，IGF2BP2通过以m6A依赖的方式稳定PRMT6的信使RNA（mRNA）来调控其表达。PRMT6进一步通过在脂质转运蛋白MFSD2A（MFSD2A）的启动子区域建立非活性的组蛋白H3精氨酸2双甲基化（H3R2me2a）修饰，抑制其基因表达。敲除PRMT6与IGF2BP2会上调MFSD2A的表达，进而增加细胞对二十二碳六烯酸（docosahexaenoic acid）的摄取能力。综上，本研究揭示了IGF2BP2-PRMT6-MFSD2A信号轴在急性髓系白血病发生发展中的关键作用，并为靶向白血病干细胞的治疗提供了极具潜力的策略。整体实验设计：急性髓系白血病细胞系Molm13的RNA测序（RNA-seq）分析。