RBM15B recognizes H3K79me2 to guide selective m(6)A-modification of mRNA and enhance oncoprotein translation in MLL-r leukemia.

The distribution of N(6)-methyladenosine (m(6)A) controls its substrate RNA fate, playing key roles in various biological processes. However, the mechanism underlying site-selective m(6)A 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 m(6)A 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 m(6)A 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-m(6)A axis inhibits the survival of leukemia cells and promotes cell differentiation, and impairs hematological malignancies. This study uncovers a novel selective m(6)A deposition mechanism mediated by H3K79me2 and RBM15B, highlighting promising therapeutic targets for hematological malignancies.