IDH1/IDH2 mutations found in glioma and AML produce the oncometabolite 2-hydroxyglutarate (2-HG). What is the primary mechanism by which 2-HG drives tumorigenesis?

• A 2-HG activates mTOR complex 1, promoting cell growth
• B 2-HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases (including TET2 and Jumonji-domain histone demethylases), causing DNA and histone hypermethylation ✓
• C 2-HG inhibits succinate dehydrogenase, causing pseudohypoxia via HIF-1α stabilisation
• D 2-HG mimics alpha-ketoglutarate and drives constitutive HIF-1α hydroxylation, reducing angiogenesis

Explanation

Mutant IDH1/IDH2 acquires a neomorphic activity converting α-ketoglutarate (αKG) to the R-enantiomer of 2-hydroxyglutarate (2-HG) instead of isocitrate. Because 2-HG structurally resembles αKG, it competitively inhibits αKG-dependent dioxygenases including TET2 (DNA demethylase) and Jumonji-domain histone demethylases, resulting in genome-wide DNA hypermethylation and H3K27me3/H3K9me3 histone hypermethylation (CpG island methylator phenotype, CIMP). This epigenetic silencing blocks differentiation, driving a stem-cell-like state. Succinate and fumarate accumulations from SDH/FH mutations cause pseudohypoxia, a distinct mechanism.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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