title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Moriyama
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Nishii
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Perez-Andreu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.affiliation: Unidad Nacional de Oncología Pediátrica, Guatemala City, Guatemala.|Francisco Marroquin Medical School, Guatemala City, Guatemala.
authors.forename: Federico Antillon
authors.initials: FA
authors.lastname: Klussmann
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Xujie
authors.identifier: http://orcid.org/0000-0001-7213-2270
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Ting-Nien
authors.initials: TN
authors.lastname: Lin
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Keito
authors.initials: K
authors.lastname: Hoshitsuki
authors.affiliation: Department of Paediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Nersting
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kihira
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hofmann
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komada
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: McCorkle
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Lie
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Koh
authors.affiliation: Unidad Nacional de Oncología Pediátrica, Guatemala City, Guatemala.
authors.forename: Cesar Rolando
authors.initials: CR
authors.lastname: Najera
authors.affiliation: National University Cancer Institute, National University Health System, Singapore.
authors.forename: Shirley Kow-Yin
authors.initials: SK
authors.lastname: Kham
authors.affiliation: Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Isobe
authors.affiliation: National University Cancer Institute, National University Health System, Singapore.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
authors.affiliation: National University Cancer Institute, National University Health System, Singapore.
authors.forename: Edwynn Kean-Hui
authors.initials: EK
authors.lastname: Chiew
authors.affiliation: Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California, USA.
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhojwani
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Jeffries
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.|German Cancer Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Inaba
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Manabe
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hori
authors.affiliation: Department of Paediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.|Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
authors.affiliation: National University Cancer Institute, National University Health System, Singapore.|Viva University Children's Cancer Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Allen E J
authors.initials: AE
authors.lastname: Yeoh
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jun J
authors.identifier: http://orcid.org/0000-0002-0770-9659
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D056726:Genetic Association Studies; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D015122:Mercaptopurine / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D000096964:Nudix Hydrolases
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D011755:Pyrophosphatases; C543721:NUDT15 protein, human; D000096964:Nudix Hydrolases