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

Abstract

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.

Keywords: ALKBH5; N(6)-methyladenosine; acute myeloid leukemia; chromatin accessibility; hematopoiesis; leukemia stem cell.