IDH1 and IDH2 mutations in gliomas and AML produce 2-hydroxyglutarate (2-HG), an oncometabolite. The primary mechanism by which 2-HG drives oncogenesis is:
- A Competitive inhibition of alpha-ketoglutarate-dependent dioxygenases including TET2 and histone demethylases ✓
- B Direct activation of mTORC1 pathway
- C Inhibition of pyruvate dehydrogenase complex
- D Accumulation of succinate blocking electron transport chain
Explanation
Mutant IDH1/2 catalyzes an aberrant reaction: alpha-ketoglutarate + NADPH → 2-hydroxyglutarate (2-HG) + NADP+. 2-HG is a structural analogue of alpha-ketoglutarate (alpha-KG) and competitively inhibits the large family of alpha-KG-dependent dioxygenases, including: (1) TET2 (DNA hydroxymethylation), leading to DNA hypermethylation and gene silencing; (2) KDM histone lysine demethylases, causing aberrant histone methylation (H3K9me3, H3K27me3); (3) prolyl hydroxylase (stabilizing HIF-1 alpha). The resulting epigenetic dysregulation blocks normal differentiation, driving the hypermethylator phenotype (CpG island methylator phenotype, CIMP) seen in gliomas and AML. Succinate accumulation (option D) occurs in SDH-mutant tumors via a similar but distinct mechanism.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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Written and medically reviewed by the StethoPrep medical team.