Nudt15-KO Mouse

NUDT15, also known as MTH2, is an enzyme that catalyzes the dephosphorylation of 6-thioguanosine triphosphate (6-TGTP) and 6-thio-deoxyguanosine triphosphate (6-TdGTP), which are active metabolites of thiopurine medications. It is an additional component of the thiopurine metabolism pathway [1]. Thiopurines are widely used in treating childhood leukemia, inflammatory bowel disease, and autoimmune disorders [1]. Genetic variation in NUDT15 that leads to decreased activity is a contributor to thiopurine toxicity, especially in Asian and Latino populations where its variants are more common than TPMT variants [1].

In a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-), excessive hematopoietic toxicity was observed, and more metabolite (DNA-TG) accumulated compared to wild-type or single heterozygous mice. This was mitigated by genotype-guided dose titration of mercaptopurine (MP), suggesting the importance of considering NUDT15 in personalized MP therapy [2].

In conclusion, NUDT15 plays a crucial role in thiopurine metabolism, and its genetic variation significantly impacts the risk of thiopurine-induced toxicity. The Tpmt/Nudt15 combined heterozygous mouse model has provided insights into the additive effects of NUDT15 and TPMT on thiopurine toxicity in the context of acute lymphoblastic leukemia treatment, highlighting the importance of genotype-guided dosing to mitigate toxicity [2].

References:

1. Moyer, Ann M. 2021. NUDT15: A bench to bedside success story. In Clinical biochemistry, 92, 1-8. doi:10.1016/j.clinbiochem.2021.02.007. https://pubmed.ncbi.nlm.nih.gov/33675810/

2. Maillard, Maud, Nishii, Rina, Yang, Wenjian, Haidar, Cyrine E, Yang, Jun J. . Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations. In Journal of the National Cancer Institute, 116, 702-710. doi:10.1093/jnci/djae004. https://pubmed.ncbi.nlm.nih.gov/38230823/