# Mutant IDH / 2-hydroxyglutarate

Source: https://onco.cc/pathways/idh-2hg/  
OnCo record `idh-2hg` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A single mutation in a metabolic enzyme (IDH1 or IDH2) makes cells pour out a molecule they should never make, 2-hydroxyglutarate. It jams the machinery that erases chemical marks on DNA and histones, so blood and brain cells get stuck before they mature. Pills that block the mutant enzyme let them mature again.

## Summary

Wild-type IDH1 (cytoplasm) and IDH2 (mitochondria) convert isocitrate to α-ketoglutarate. Hotspot mutations (IDH1 R132, IDH2 R140/R172) give the enzyme a new activity: reducing α-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate, which reaches millimolar levels. 2-HG competitively inhibits α-ketoglutarate-dependent dioxygenases: the TET family of DNA demethylases (producing the CpG island hypermethylator phenotype, G-CIMP, in glioma and a TET2-like phenotype in AML), the JmjC histone demethylases and prolyl hydroxylases. The result is a block in differentiation rather than fast proliferation, which is why IDH-mutant gliomas are slow-growing and why the drugs work by differentiation. Mutant-selective inhibitors ivosidenib (IDH1), olutasidenib (IDH1), enasidenib (IDH2) and the brain-penetrant dual inhibitor vorasidenib are approved: ivosidenib in AML, cholangiocarcinoma and MDS; vorasidenib for grade 2 IDH-mutant glioma after the INDIGO trial. Differentiation syndrome is the class toxicity; resistance arises through second-site IDH mutations and switching from IDH1 to IDH2 (or back).

## Fields

- Kind: Pathway
- Last checked: 2026-09-04
- Analogy: A factory machine (IDH) that is supposed to make one part is bent so it makes a rogue part (2-HG) that gums up the erasers (TET, histone demethylases) which normally wipe old instructions off the blueprint. Cells cannot read the 'grow up' instructions and stay immature. The inhibitors straighten the machine; the erasers work again and the cells mature.
- Interventions: Ivosidenib (IDH1) for relapsed AML, first-line AML with azacitidine (AGILE), IDH1-mutant cholangiocarcinoma and MDS; Olutasidenib (IDH1) and enasidenib (IDH2) for relapsed or refractory AML; Vorasidenib (dual IDH1/2, brain-penetrant) for residual or recurrent grade 2 IDH-mutant astrocytoma and oligodendroglioma (INDIGO); Differentiation syndrome is the class toxicity; steroids and hydroxyurea manage it; Combination with venetoclax and azacitidine, and with PARP inhibitors (2-HG induces a homologous-recombination defect), under study

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Isocitrate_dehydrogenase
- Wikipedia: https://en.wikipedia.org/wiki/Isocitrate_dehydrogenase

## Connected records

- cancers: [Acute myeloid leukaemia](https://onco.cc/cancers/aml/), [Biliary tract cancer (cholangiocarcinoma)](https://onco.cc/cancers/cholangiocarcinoma/), [Glioma & glioblastoma](https://onco.cc/cancers/glioblastoma/), [Myelodysplastic syndromes / neoplasms (MDS)](https://onco.cc/cancers/mds/), [Nasal cavity and paranasal sinus cancers (including esthesioneuroblastoma)](https://onco.cc/cancers/sinonasal/)
- targets: [IDH1 / IDH2](https://onco.cc/targets/idh/), [TET2](https://onco.cc/targets/tet2/)
- drugs: [Enasidenib](https://onco.cc/drugs/enasidenib/), [Ivosidenib](https://onco.cc/drugs/ivosidenib/), [Olutasidenib](https://onco.cc/drugs/olutasidenib/), [Vorasidenib](https://onco.cc/drugs/vorasidenib/)
- pathways: [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Glioma (KEGG map)](https://onco.cc/pathways/glioma-signalling/)
- trials: [INDIGO](https://onco.cc/trials/indigo/)
- roadmaps: [Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome](https://onco.cc/roadmaps/epigenetics-roadmap/)

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JSON: https://onco.cc/api/v1/entities/idh-2hg.json