Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [MeRIP-seq]. Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [MeRIP-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: MeRIP-seq of LIC and BLAST cells sorted from WT mice BM leukemia cells.

我们的研究数据显示，RNA m6A（N6-甲基腺嘌呤）在白血病发生过程中呈现显著的动态转变，并参与白血病干细胞（LSCs）干性特征的获得。本研究发现，m6A阅读蛋白IGF2BP2与蛋白质精氨酸甲基转移酶PRMT6在白血病干细胞干性特征的获得中发挥关键作用。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）的疾病进展。机制层面研究表明，IGF2BP2通过依赖m6A的方式稳定PRMT6的mRNA，进而调控其表达。PRMT6还可通过在脂质转运蛋白MFSD2A的启动子区域建立非活性型组蛋白H3精氨酸2位点二甲基化（H3R2me2a）修饰，抑制MFSD2A的表达。敲除PRMT6与IGF2BP2会上调MFSD2A的表达，进而提升细胞对二十二碳六烯酸（DHA）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策略提供了极具潜力的新思路。实验整体设计：从野生型（WT）小鼠骨髓（BM）白血病细胞中分选白血病起始细胞（LIC）与白血病母细胞（BLAST），并对其开展甲基化RNA免疫沉淀测序（MeRIP-seq）。