Evaluation Of Nudt15 -Guided Thiopurine Dose Individualization In Vivo Using Crispr/Cas9-Edited Mouse Model

Prolonged exposure to thiopurines (e.g., 6-mercaptopurine [MP]) is an essential component of curative therapy of acute lymphoblastic leukemia (ALL) in children and adults. However, this class of drugs are also associated with frequent dose-limiting hematopoietic and liver toxicities, at least in part explained by genetic polymorphisms in metabolizing enzymes such as TPMT . In fact, pre-emptive TPMT- genotype guided thiopurine dose reduction has been implemented in clinical practice and shown to effectively mitigate toxicity without compromising therapeutic efficacy. More recently, we and others identified NUDT15 as a novel genetic determinant of thiopurine toxicity (Nature Genetics , 2014 and 2016), particularly in Asian and Hispanic populations. While results from correlative studies in patients point to potential effectiveness of NUDT15 -genotype based thiopurine individualization, the exact dosing algorithm remains unknown and there have been no laboratory models to test such strategies. To this end, we established a Nudt15 knockout mouse model on FVB/N background by CRISPR-Cas9 genome editing, with which we systematically evaluated NUDT15 -genotype directed thiopurine dose reduction and its effects on hematopoietic toxicity in vivo .