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

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.