RBM15B recognizes H3K79me2 to guide selective m6A-modification of mRNA and enhance oncoprotein translation in MLL-r leukemia

The distribution of N⁶-methyladenosine (m⁶A) controls its substrate RNA fate, playing key roles in various biological processes. However, the mechanism underlying site-selective m⁶A deposition of RNAs, especially in the start codon regions, and the role in epigenetic information transduction connecting tumorigenesis remain largely unknown. Here, we identified RBM15B mainly modulates m⁶A modifications in the 5'untranslated regions (UTRs) and around the start codons of mRNAs transcribed. This process is guided by H3K79me2 histone methylation, a critical epigenetic modification in mixed lineage leukemia. We show that the H47 of RBM15B is a key residue for the recognition of H3K79me2. The selective m⁶A modification orchestrated by the H3K79me2-RBM15B axis enhances translation efficiency of oncogenic transcripts, and promotes self-renewal of leukemic stem cells and leukemia maintenance. We further demonstrate that blockade of the H3K79me2-RBM15B-m⁶A axis inhibits the survival of leukemia cells and promotes cell differentiation, and impairs hematological malignancies. This study uncovers a novel selective m⁶A deposition mechanism mediated by H3K79me2 and RBM15B, highlighting promising therapeutic targets for hematological malignancies.