NUDT15 Polymorphisms Alter Thiopurine Metabolism and Hematopoietic Toxicity

Abstract

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.

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 14 September 2016

Publication date (Electronic): 15 February 2016

Publication date (Print): April 2016

Publication date PMC-release: 01 October 2016

Volume: 48

Issue: 4

Pages: 367-373

Affiliations

[1 ]Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

[2 ]Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan

[3 ]Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan

[4 ]Unidad Nacional de Oncología Pediátrica, Guatemala City, Guatemala

[5 ]Francisco Marroquin Medical School, Guatemala City, Guatemala

[6 ]School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

[7 ]Department of Paediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark

[8 ]Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany

[9 ]Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany

[10 ]Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan

[11 ]Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan

[12 ]National University Cancer Institute, National University Health System, Singapore

[13 ]Graduate School of Medicine and Faculty of Medicine, the University of Tokyo, Tokyo, Japan

[14 ]Department of Pediatrics, Children’s Hospital of Los Angeles, Los Angeles, California, USA

[15 ]Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

[16 ]German Cancer Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany

[17 ]Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany

[18 ]Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

[19 ]Department of Pediatrics, St. Luke’s International Hospital, Tokyo, Japan

[20 ]The Institute of Clinical Medicine, the University of Copenhagen, Copenhagen, Denmark

[21 ]Viva-University Children’s Cancer Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Author notes

Correspondence: Jun J. Yang, PhD, Department of Pharmaceutical Sciences, Hematologic Malignancies Program, Comprehensive Cancer Center, St. Jude Children’s Research Hospital, MS313, 262 Danny Thomas Place Memphis, Tennessee 38105-3678, jun.yang@ 123456stjude.org , Phone: [phone]

[*]

These authors contributed equally

Article

Accession ID: PMC5029084 Pmcid ID: PMC5029084 Pmc-uid ID: 5029084 Manuscript ID: nihpa813033

DOI: 10.1038/ng.3508

PMC ID: 5029084

PubMed ID: 26878724

Categories

Subject: Article