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NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.

ABSTRACT: 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.

SUBMITTER: Moriyama T

PROVIDER: S-EPMC5029084 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.

Moriyama Takaya T Nishii Rina R Perez-Andreu Virginia V Yang Wenjian W Klussmann Federico Antillon FA Zhao Xujie X Lin Ting-Nien TN Hoshitsuki Keito K Nersting Jacob J Kihira Kentaro K Hofmann Ute U Komada Yoshihiro Y Kato Motohiro M McCorkle Robert R Li Lie L Koh Katsuyoshi K Najera Cesar Rolando CR Kham Shirley Kow-Yin SK Isobe Tomoya T Chen Zhiwei Z Chiew Edwynn Kean-Hui EK Bhojwani Deepa D Jeffries Cynthia C Lu Yan Y Schwab Matthias M Inaba Hiroto H Pui Ching-Hon CH Relling Mary V MV Manabe Atsushi A Hori Hiroki H Schmiegelow Kjeld K Yeoh Allen E J AE Evans William E WE Yang Jun J JJ

Nature genetics 20160215 4

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 ...[more]

PMID: 26878724

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Project description:Thiopurines, such as 6-mercaptopurine (6-MP), are widely used as cytotoxic agents and immunosuppressants for leukemia and autoimmune or inflammatory diseases. A nonsynonymous single nucleotide polymorphism (p.Arg139Cys; R139C) of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene causes the loss of thiopurine detoxification, inducing myelosuppression. To understand such hematotoxicity, we investigate the effects of NUDT15 R139C on hematopoietic stem cells (HSCs) upon thiopurine administration. Using previously established Nudt15R138C knock-in mice, which mimic myelosuppression in NUDT15R139C homozygous or heterozygous patients following thiopurine administration, we investigated the numerical changes of HSCs and hematopoietic progenitor cells following 6-MP administration using in vivo flowcytometry and ex vivo HSC expansion. Genes differentially expressed between Nudt15+/+ HSCs and Nudt15R138C/R138C HSCs were identified using RNA-sequencing before the emergence of 6-MP-induced HSC-damage. Gene Ontology (GO) and Transcriptional Regulatory Relationships Unraveled by Sentence-based Text Mining (TRRUST) analyses were performed to elucidate the molecular effects of 6-MP on HSCs. In Nudt15R138C/R138C mice, 6-MP induced exhaustion of HSCs faster than that of multipotent progenitors and as fast as that of myeloid-committed progenitors. Ex vivo-expanded Nudt15R138C/R138C HSCs were dose- and time-dependently damaged by 6-MP. GO analysis identified the DNA damage response and cell cycle process as the most strongly influenced processes in Nudt15R138C/R138C HSCs. TRRUST analysis revealed that the Trp53-regulated transcriptional regulatory network is influenced prior to HSC exhaustion in Nudt15R138C/R138C HSCs. The loss of NUDT15 thiopurine detoxification enhances thiopurine-mediated DNA damage via the Trp53 networks in HSCs. Therefore, caution is required in long-term thiopurine use in patients with NUDT15 R139C in view of its adverse effects on HSCs in the form of DNA damage.

Dataset Information

NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.

Publications

NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.

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