NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.
NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.
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DOI：
10.1038/ng.3508
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发表时间：
2016-04
期刊：
影响因子：
30.8
通讯作者：
Yang, Jun J.
中科院分区：
文献类型：
--
作者：
Moriyama, Takaya;Nishii, Rina;Perez-Andreu, Virginia;Yang, Wenjian;Klussmann, Federico Antillon;Zhao, Xujie;Lin, Ting-Nien;Hoshitsuki, Keito;Nersting, Jacob;Kihira, Kentaro;Hofmann, Ute;Komada, Yoshihiro;Kato, Motohiro;McCorkle, Robert;Li, Lie;Koh, Katsuyoshi;Najera, Cesar Rolando;Kham, Shirley Kow-Yin;Isobe, Tomoya;Chen, Zhiwei;Chiew, Edwynn Kean-Hui;Bhojwani, Deepa;Jeffries, Cynthia;Lu, Yan;Schwab, Matthias;Inaba, Hiroto;Pui, Ching-Hon;Relling, Mary V.;Manabe, Atsushi;Hori, Hiroki;Schmiegelow, Kjeld;Yeoh, Allen E. J.;Evans, William E.;Yang, Jun J.
作为广泛应用的抗癌和免疫抑制药物，硫嘌呤类药物由于频繁的毒性作用而导致治疗指数较低，部分原因是TPMT基因的多态性。最近的研究证实，胚系NUDT15变异是硫嘌呤不耐受的另一个关键决定因素，但潜在的分子机制及其临床意义仍不清楚。在危地马拉、新加坡和日本参加急性淋巴细胞白血病临床试验的270名儿童中，我们发现了4个NUDT15编码变体(p.Arg139Cys，p.Arg139His，p.Val18Ile，p.Val18_Val19insGlyVal)，导致核苷酸二磷酸酶活性丧失74.4%-100%。在三个队列中，功能丧失的NUDT15二倍型与硫嘌呤不耐受一致相关(分别为P=0.021、2.1×10−5和0.0054；Meta分析P=4.45×10−8，等位基因效应大小=−11.5)。机制上，NUDT15在体外灭活了硫代谢物并降低了其细胞毒性，NUDT15等位基因缺陷的患者表现出过多的硫嘌呤活性代谢物和毒性。综上所述，我们的结果表明，整合NUDT15变体的综合药物遗传学模型可能会为个性化的硫嘌呤治疗提供信息。
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.
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