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

## TL;DR

The paper shows how RBM15B uses a histone mark to guide RNA methylation, promoting cancer protein production in leukemia.

## Contribution

RBM15B's role in H3K79me2-guided m6A modification and its impact on oncoprotein translation in leukemia is newly revealed.

## Key findings

- RBM15B modifies m6A in 5′UTRs and start codons of mRNAs, guided by H3K79me2.
- Blocking the H3K79me2-RBM15B-m6A axis reduces leukemia cell survival and promotes differentiation.
- RBM15B enhances oncoprotein translation efficiency and leukemic stem cell self-renewal.

## Abstract

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.

The mechanisms underlying site-selective N6-methyladenosine (m6A) deposition at RNAs and its role in epigenetic information transduction remain unclear. Here, RBM15B is identified as a histone methylation-guided regulator of m6A modifications of mRNAs, enhancing translation of oncogenic transcripts in leukemia.

RNA-binding protein RBM15B is enriched in mixed lineage leukemia (MLL) and regulates selective m6A modification of RNAs.RBM15B-mediated m6A deposition at start codon regions and recruitment of the methyltransferase complex depend on H3K79me2.RBM15B-guided selective m6A RNA modification promotes oncoprotein translation efficiency.Targeting the H3K79me2-RBM15B-m6A axis impairs leukemic cell self-renewal and leukemogenesis in vivo.

RNA-binding protein RBM15B is enriched in mixed lineage leukemia (MLL) and regulates selective m6A modification of RNAs.

RBM15B-mediated m6A deposition at start codon regions and recruitment of the methyltransferase complex depend on H3K79me2.

RBM15B-guided selective m6A RNA modification promotes oncoprotein translation efficiency.

Targeting the H3K79me2-RBM15B-m6A axis impairs leukemic cell self-renewal and leukemogenesis in vivo.

RNA-binding protein RBM15B integrates histone methylation and site-specific RNA methylation fueling oncoprotein synthesis and hematological malignancies.