R140Q

R140Q designates a specific missense mutation in the isocitrate dehydrogenase 2 (IDH2) gene, in which the arginine at codon 140 is replaced by glutamine. IDH2 encodes a mitochondrial NADP‑dependent enzyme that catalyzes the conversion of isocitrate to α‑ketoglutarate (α‑KG) while producing NADPH. The R140Q substitution alters the enzyme’s active site, conferring a neomorphic activity that reduces α‑KG to the oncometabolite D‑2‑hydroxyglutarate (D‑2HG). Accumulation of D‑2HG interferes with α‑KG‑dependent dioxygenases, affecting DNA and histone demethylation, hypoxia signaling, and collagen maturation, thereby contributing to epigenetic dysregulation and cellular transformation.

Clinically, the IDH2 R140Q mutation is most frequently identified in myeloid malignancies, particularly acute myeloid leukemia (AML), where it occurs in roughly 8–12 % of patients. It is also detected, albeit less commonly, in myelodysplastic syndromes, cholangiocarcinoma, and other solid tumors. In AML, the presence of R140Q is associated with distinct molecular subtypes and may influence prognosis; some studies suggest a modestly favorable outcome compared with wild‑type IDH2, while others report variable risk depending on co‑mutational context.

The mutation provides a therapeutic target. The selective IDH2 inhibitor enasidenib (AG‑221) received regulatory approval for relapsed or refractory AML harboring IDH2 mutations, including R140Q, and has demonstrated hematologic improvement and durable remissions in clinical trials. Molecular testing for IDH2 R140Q is routinely performed using next‑generation sequencing panels or allele‑specific PCR to guide diagnosis, risk stratification, and treatment decisions. Ongoing research explores combination strategies and resistance mechanisms associated with IDH2‑directed therapy.