IDH1 and IDH2 gain-of-function mutations in gliomas and AML produce a novel oncometabolite. Which metabolite is produced and what is its principal oncogenic mechanism?

• A Succinate; inhibits prolyl hydroxylases stabilising HIF-1alpha
• B 2-hydroxyglutarate (2-HG); competitively inhibits alpha-ketoglutarate-dependent dioxygenases causing hypermethylation ✓
• C Fumarate; causes epithelial-mesenchymal transition via mTOR activation
• D Oxaloacetate; drives reverse TCA flux and lipogenesis

Explanation

Mutant IDH1/2 acquires a neomorphic activity, reducing alpha-ketoglutarate (alpha-KG) to the oncometabolite 2-hydroxyglutarate (2-HG). 2-HG competitively inhibits alpha-KG-dependent dioxygenases including TET2 (DNA demethylase) and histone demethylases (KDM family), causing a CpG island methylator phenotype (CIMP) and widespread epigenetic silencing of tumour suppressor genes. Succinate and fumarate (accumulated in SDH/FH-deficient tumours) also inhibit prolyl hydroxylases but via a separate mechanism.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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