IDH1 and IDH2 mutations in gliomas and AML produce the oncometabolite 2-hydroxyglutarate (2-HG). The MECHANISM by which 2-HG drives tumorigenesis is:

• A 2-HG directly activates HIF-1alpha by inhibiting prolyl hydroxylases
• B 2-HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases (TET methylcytosine hydroxylases and KDMs), causing hypermethylation of DNA and histones ✓
• C 2-HG accumulates in mitochondria and inhibits the TCA cycle at the succinate dehydrogenase step
• D 2-HG activates mTOR signalling by mimicking leucine at the mTORC1 complex

Explanation

Mutant IDH1/IDH2 neomorphically converts alpha-ketoglutarate (2-oxoglutarate) to 2-HG using NADPH. 2-HG is a structural analogue of alpha-KG and competitively inhibits alpha-KG-dependent dioxygenases, particularly TET2 (which demethylates 5-methylcytosine) and histone demethylases (KDM family). This results in a CpG island methylator phenotype (CIMP) — widespread hypermethylation of DNA and histones — silencing tumor suppressor genes and blocking differentiation. 2-HG does not activate HIF-1alpha (that is succinate/fumarate which inhibit PHDs).

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.