Mutant IDH1 and 2-hydroxyglutarate oncometabolite signaling

Current understanding

Mutant IDH1 produces the oncometabolite 2-hydroxyglutarate (2-HG), which inhibits α-ketoglutarate-dependent dioxygenases including TET2 and histone demethylases, driving aberrant DNA and histone methylation and blocking myeloid differentiation. IDH1 mutations occur in a subset of higher-risk MDS, CMML, and advanced/blast-phase MPN, where they contribute to disease progression. Selective IDH1 inhibitors such as olutasidenib suppress 2-HG production and restore differentiation, and are now being evaluated in combination with hypomethylating agents in IDH1-mutated myeloid malignancies.

Evidence log

• 2026-07-09 — Glutamate accumulation in myelofibrosis microenvironment rewires mesenchymal stromal cells metabolic and epigenetic profiles.: cross-connection with glutamate-mglur5-fumarate-msc-rewiring: Fumarate in MSCs and 2-HG in mutant-IDH clones represent parallel oncometabolite-driven epigenetic mechanisms in MPN, one acting in stroma and the other in hematopoietic cells. (novelty: 5)
• 2026-05-20 — A Phase 2 Study Evaluating Olutasidenib in Combination With Hypomethylating Agents in Patients With IDH1-mutated Higher-risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Advanced Myeloproliferative Neoplasm: cross-connection with dna-hypomethylation-epigenetic-reprogramming: Olutasidenib + HMA combinations test mechanistic synergy between blocking 2-HG–driven hypermethylation (IDH1 inhibition) and pharmacologic DNA hypomethylation in IDH1-mutated MDS/CMML/MPN. (novelty: 3)

Open questions

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