NUDT15 Variants Alter Thiopurine-Associated Hematopoietic Toxicity

Thiopurines are widely used to induce immunosuppression and reduce proliferation of cancer, particularly acute lymphoblastic leukemia (ALL), and are converted to thioguanine triphosphate and incorporated into double-stranded DNA to form 6-thioguanine DNA (DNA-TG), causing a futile mismatch repair response and resulting in apoptosis. However, thiopurines exhibit a narrow therapeutic range due to thiopurine-related frequent hematopoietic toxicity, which has been shown to be associated with a nudix-type motif 15 (NUDT15) variant, c.415C>T, in patients with pediatric ALL. To investigate the molecular mechanisms underlying the role of NUDT15 variants in modulating thiopurine toxicity, Moriyama and colleagues performed exonic sequencing of NUDT15 in 270 pediatric patients with ALL and identified four variants, including c.415C>T. Sequence analysis revealed that the c.415C>T variant and the three newly discovered variants – c.416G>T, c.52G>A, and c.36_37insGGAGTC – affected residues arginine 139 and valine 18, which may result in conformational changes of NUDT15. All four NUDT15 variants exhibited significantly decreased enzymatic activity, and pairwise combinations of the NUDT15 variants revealed a gene dosage effect on NUDT15 activity. NUDT15 diplotypes corresponding to low, intermediate, and normal levels of NUDT15 activity were associated with tolerance to correspondingly increasing dosages of the thioguanine mercaptopurine, which is a standard-of-care treatment for patients with ALL. Mechanistically, NUDT15 inactivated thiopurine metabolites, which resulted in decreased levels of DNA-TG and thiopurine-induced apoptosis. In patients with ALL, the ratio of DNA-TG to unit of mercaptopurine dosage, which corresponded to the amount of DNA-TG converted from mercaptopurine, was directly related to NUDT15 diplotype. Taken together, these results suggest that NUDT15 variants enhance sensitivity to thiopurines and that preemptive NUDT15 genotyping may inform individualized thiopurine therapy.

Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 2016 Feb 15 [Epub ahead of print].