Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis

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. [Display omitted] •ALKBH5 is highly expressed in AML and associated with poor prognosis•ALKBH5 is selectively required for LSCs but dispensable for normal HSCs•KDM4C regulates ALKBH5 expression by increasing chromatin accessibility to MYC and Pol II•ALKBH5 affects mRNA stability of AXL in an m6A-dependent manner Wang et al. find that ALKBH5 is specifically required for maintaining the function of acute myeloid leukemia (AML) stem cells but not normal hematopoietic stem cells and reveal KDM4C-ALKBH5-AXL signaling axis in AML development and maintenance. These findings lay the foundation for targeting ALKBH5 for AML therapy.