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

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月2日

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  • Tian-Qi Chen,
  • Yu-Meng Sun,
  • Shun-Xin Zhu,
  • Xiao-Tong Chen,
  • Ke-Jia Pu,
  • Heng-Jing Huang,
  • Qi Pan,
  • Jun-Yi Lian,
  • Wei Huang,
  • Ke Fang,
  • Xue-Qun Luo,
  • Li-Bin Huang,
  • Yue-Qin Chen,
  • Wen-Tao Wang

摘要

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.