N⁶-methyladenosine (m⁶A) is a commonly present modification of mammalian mRNAs and plays key roles in various cellular processes. m⁶A modifiers catalyze this reversible modification. However, the underlying mechanisms by which these m⁶A modifiers are regulated remain elusive. Here we show that expression of m⁶A demethylase ALKBH5 is regulated by chromatin state alteration during leukemogenesis of human acute myeloid leukemia (AML), and ALKBH5 is required for maintaining leukemia stem cell (LSC) function but is dispensable for normal hematopoiesis. Mechanistically, KDM4C regulates ALKBH5 expression via increasing chromatin accessibility of ALKBH5 locus, by reducing H3K9me3 levels and promoting recruitment of MYB and Pol II. Moreover, ALKBH5 affects mRNA stability of receptor tyrosine kinase AXL in an m⁶A-dependent way. Thus, our findings link chromatin state dynamics with expression regulation of m⁶A modifiers and uncover a selective and critical role of ALKBH5 in AML that might act as a therapeutic target of specific targeting LSCs.

N ^6-甲基腺苷（m ⁶ A）是哺乳动物mRNA普遍存在的修饰形式，在各种细胞过程中起关键作用。m ⁶ A改性剂催化这种可逆改性。然而，调控这些m ⁶ A修饰剂的基本机制仍然难以捉摸。在这里，我们显示了m ⁶ A脱甲基酶ALKBH5的表达受人类急性髓细胞白血病（AML）白血病发生过程中染色质状态改变的调节，而ALKBH5是维持白血病干细胞（LSC）功能所必需的，但对于正常的造血作用却是必不可少的。从机制上讲，KDM4C通过增加ALKBH5的染色质可及性来调节ALKBH5的表达通过降低H3K9me3水平并促进招募MYB和Pol II来实现这一目标。此外，ALKBH5以m ⁶ A依赖的方式影响受体酪氨酸激酶AXL的mRNA稳定性。因此，我们的发现将染色质状态动态与m ⁶ A修饰子的表达调控联系起来，并揭示了ALKBH5在AML中的选择性和关键作用，而AML可能充当特定靶向LSC的治疗靶标。