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NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity

2016; Nature Portfolio; Volume: 48; Issue: 4 Linguagem: Inglês

10.1038/ng.3508

1546-1718

Takaya Moriyama, Rina Nishii, Virginia Pérez-Andreu, Wenjian Yang, Federico Antillón‐Klussmann, Xujie Zhao, Ting-Nien Lin, Keito Hoshitsuki, Jacob Nersting, Kentaro Kihira, Ute Hofmann, Yoshihiro Komada, Motohiro Kato, J. Robert McCorkle, Lie Li, Katsuyoshi Koh, Cesar Najera, Shirley Kow‐Yin Kham, Tomoya Isobe, Zhiwei Chen, Edwynn Kean-Hui Chiew, Deepa Bhojwani, Cynthia Jeffries, Yan Lu, Matthias Schwab, Hiroto Inaba, Ching‐Hon Pui, Mary V. Relling, Atsushi Manabe, Hiroki Hori, Kjeld Schmiegelow, Allen Eng Juh Yeoh, William E. Evans, Jun J. Yang,

Adolescent and Pediatric Healthcare

Jun Yang and colleagues perform targeted sequencing of NUDT15 and identify loss-of-function variants associated with thiopurine intolerance. Functionally, they show that NUDT15 inactivates thiopurine metabolites, providing a mechanism to explain the association between NUDT15 loss-of-function variants and thiopurine toxicity. Widely used as anticancer and immunosuppressive agents, thiopurines have narrow therapeutic indices owing to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and the clinical implications of this pharmacogenetic association remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore and Japan, we identified four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile and p.Val18_Val19insGlyVal) that resulted in 74.4–100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across the three cohorts (P = 0.021, 2.1 × 10−5 and 0.0054, respectively; meta-analysis P = 4.45 × 10−8, allelic effect size = −11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased thiopurine cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive levels of thiopurine active metabolites and toxicity. Taken together, these results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.