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Background <p>Mitochondrial metabolism-driven epigenetic modifications have emerged as crucial regulators for acute myeloid leukemia (AML) progression, linking metabolic activity in leukemic stem cells to epigenetically controlled transcriptional programs that drive oncogenic gene expression.</p> Results <p>Here, by integrating proteomic and transcriptomic data, we identified six genes whose expression were able to predict outcome in AML. Among these, IDH3B was highly expressed in leukemic stem cells and associated with poor prognosis. Functional studies revealed that IDH3B deletion in KMT2A-rearranged AML increased global protein succinylation, reduced acetylation, and sensitized cells to the menin–KMT2A inhibitor, both in vitro and in vivo. Mechanistically, loss of IDH3B, by increasing histone succinylation and reducing H3K79 methylation at the MYC promoter, amplified Revumenib-induced transcriptional repression of MYC.</p> Conclusions <p>These findings establish IDH3B as a key metabolic–epigenetic regulator in AML and highlight it as a potential synergistic target to enhance menin inhibition therapy.</p>

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TCA-controlled histone succinylation identifies IDH3B as a prognostic and therapeutic target in AML

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月5日

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  • Minhui Shi,
  • Kepeng Yang,
  • Hao Ding,
  • Na Zhao,
  • Jiewen Ma,
  • Aijie Huang,
  • Yun Wang,
  • Xiaoyu Zhu,
  • Domenico Iuso,
  • Mengqing Gao

摘要

Background

Mitochondrial metabolism-driven epigenetic modifications have emerged as crucial regulators for acute myeloid leukemia (AML) progression, linking metabolic activity in leukemic stem cells to epigenetically controlled transcriptional programs that drive oncogenic gene expression.

Results

Here, by integrating proteomic and transcriptomic data, we identified six genes whose expression were able to predict outcome in AML. Among these, IDH3B was highly expressed in leukemic stem cells and associated with poor prognosis. Functional studies revealed that IDH3B deletion in KMT2A-rearranged AML increased global protein succinylation, reduced acetylation, and sensitized cells to the menin–KMT2A inhibitor, both in vitro and in vivo. Mechanistically, loss of IDH3B, by increasing histone succinylation and reducing H3K79 methylation at the MYC promoter, amplified Revumenib-induced transcriptional repression of MYC.

Conclusions

These findings establish IDH3B as a key metabolic–epigenetic regulator in AML and highlight it as a potential synergistic target to enhance menin inhibition therapy.