Takaya Moriyama 1 , 2 , Rina Nishii 1 , 3 , Virginia Perez-Andreu 1 , Wenjian Yang 1 , Federico Antillon Klussmann 4 , 5 , Xujie Zhao 1 , Ting-Nien Lin 1 , Keito Hoshitsuki 1 , 6 , Jacob Nersting 7 , Kentaro Kihira 2 , Ute Hofmann 8 , 9 , Yoshihiro Komada 2 , Motohiro Kato 10 , Robert McCorkle 1 , Lie Li 1 , Katsuyoshi Koh 11 , Cesar Rolando Najera 4 , Shirley Kow-Yin Kham 12 , Tomoya Isobe 13 , Zhiwei Chen 12 , Edwynn Kean-Hui Chiew 12 , Deepa Bhojwani 14 , Cynthia Jeffries 15 , Yan Lu 15 , Matthias Schwab 8 , 9 , 16 , 17 , Hiroto Inaba 18 , Ching-Hon Pui 18 , Mary V. Relling 1 , Atsushi Manabe 19 , Hiroki Hori 2 , Kjeld Schmiegelow 7 , 20 , Allen E. J. Yeoh 12 , 21 , William E. Evans 1 , Jun J. Yang 1
15 February 2016
Widely used as anti-cancer and immunosuppressive agents, thiopurines have narrow therapeutic indices due 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 its clinical implications remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore, and Japan, we identified 4 NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile, 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 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 its cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive thiopurine active metabolites and toxicity. Taken together, our results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.