Warburg effect describes the preferential use of aerobic glycolysis by cancer cells even in the presence of oxygen. The oncometabolite 2-hydroxyglutarate (2-HG) produced in gliomas and AML with IDH1/2 mutations leads to malignant transformation primarily by:

• A Inhibiting pyruvate dehydrogenase, forcing cells toward aerobic glycolysis
• B Activating mTORC1 signalling by mimicking amino acid sufficiency
• C Directly binding and stabilising HIF-1alpha protein, inducing pseudo-hypoxic signalling
• D Competitively inhibiting alpha-ketoglutarate-dependent dioxygenases, causing hypermethylation of DNA and histones ✓

Explanation

Mutant IDH1/2 enzymes acquire a neomorphic activity, converting alpha-ketoglutarate (alpha-KG) to the oncometabolite R-2-hydroxyglutarate (2-HG). 2-HG is a structural mimic of alpha-KG and competitively inhibits alpha-KG-dependent dioxygenases including TET2 (DNA demethylase) and Jumonji histone demethylases. This leads to the CpG island methylator phenotype (CIMP) — genome-wide hypermethylation of DNA and histones — which silences tumour suppressor genes and blocks differentiation. This mechanism explains why IDH-mutant gliomas and AML show a glioma-CpG island methylator phenotype. IDH mutations are distinct from Warburg effect drivers like LDH-A upregulation.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.