N6-甲基腺苷(m6A)是哺乳动物mRNA的常见化学修饰物，并在各种生物过程中表现出高动态。然而，在白血病发生过程中，m6A RNA甲基组的动态仍然未知。在这里，我们勾勒了急性髓性白血病(AML)发展过程中包括了全面的m6A景观，并将PRMT6作为维持AML干细胞的关键因素进行了确认。我们观察到在白血病发生过程中m6A甲基组有明显的变化，并发现蛋白质精氨酸甲基转移酶PRMT6和m6A读取器IGF2BP2维持人类和小鼠白血病干细胞(LSCs)的功能。PRMT6的遗传删除或药物抑制会影响AML的发展和LSC的功能。机制上，IGF2BP2通过m6A介导方式稳定PRMT6 mRNA，PRMT6催化H3R2me2a并抑制脂质转运蛋白MFSD2A表达。PRMT6的丧失会上调MFSD2A的表达，增加二十二碳六烯酸水平，并损害LSC的维持。总的来说，我们的发现揭示了PRMT6-MFSD2A信号轴在AML发展中的关键作用，并提供了一个针对LSC的治疗策略。版权所有©2022 Elsevier Inc.。保留所有权利。

N6-methyladenosine (m6A) is a common chemical modification for mammalian mRNA and exhibits high dynamics in various biological processes. However, dynamics of m6A RNA methylome during leukemogenesis remains unknown. Here, we delineate a comprehensive m6A landscape during acute myeloid leukemia (AML) development and identify PRMT6 as a key for maintaining AML stem cells. We observe an obvious change in m6A methylome during leukemogenesis and find that protein arginine methyltransferase PRMT6 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 and LSC function. Mechanistically, IGF2BP2 stabilizes PRMT6 mRNA via m6A-mediated manner, which catalyzes H3R2me2a and suppresses lipid transporter MFSD2A expression. PRMT6 loss upregulates MFSD2A expression that increases docosahexaenoic acid levels and impairs LSC maintenance. Collectively, our findings reveal a critical role of PRMT6-MFSD2A signaling axis in AML development and provide a therapeutic strategy for targeting LSCs.Copyright © 2022 Elsevier Inc. All rights reserved.