NUDT15 encodes a nudix hydrolase that catalyzes hydrolysis of nucleoside triphosphates including dGTP, dTTP, dCTP, and their oxidized forms like 8-oxo-dGTP 1. Critically, NUDT15 hydrolyzes thiopurine derivatives including 6-thio-dGTP and 6-thio-GTP, participating in thiopurine drug catabolism 12. The enzyme may also regulate cellular isoprenoid metabolism by hydrolyzing isoprene pyrophosphates 3 and stabilize PCNA to support DNA synthesis and cell cycle progression 4. Loss-of-function NUDT15 variants are common in Asian and Hispanic populations and significantly impair thiopurine inactivation 5. This reduces degradation of active thiopurine nucleotide metabolites, increasing their incorporation into DNA and predisposing patients to myelosuppression 67. The c.415C>T variant shows strong association with thiopurine-induced leukopenia and neutropenia in acute lymphoblastic leukemia (ALL) patients, with 9-fold increased leukopenia risk and substantially reduced tolerable 6-mercaptopurine doses 89. Clinically, NUDT15 genotyping is recommended alongside TPMT testing to guide thiopurine dosing in ALL maintenance therapy 5. Patients with compound intermediate metabolizer status (TPMT/NUDT15 IM/IM) require more substantial dose reductions to mitigate toxicity 6.