IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition

Mutations in IDH1 and IDH2, which lead to the production of the oncometabolite 2-hydroxyglutarate (2HG), have been identified in various cancers, including acute myeloid leukemia (AML). These mutant enzymes drive elevated 2HG levels and induce a block in cellular differentiation—a phenotype that can be reversed using mutant-specific IDH inhibitors. To further elucidate the mechanistic role of IDH mutations in cancer, we employed the TF-1 erythroleukemia cell model expressing the IDH2 R140Q mutation. Our studies revealed that mutant IDH2 expression induces widespread histone and DNA hypermethylation, both of which are reversible upon pharmacologic inhibition of mutant enzyme activity. Histone hypermethylation was reversed rapidly within days, whereas DNA demethylation occurred more gradually over several weeks. Transcriptomic analysis uncovered gene signatures associated with leukemogenesis and lymphomagenesis, suggesting that IDH mutations selectively modulate the expression of cancer-relevant genes. Given the strong link between epigenetic regulation, gene expression, and differentiation, our findings support the therapeutic potential of IDH2 mutant inhibition to restore normal differentiation through AGI-6780 coordinated reversal of aberrant histone and DNA methylation.