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      NUDT15 Polymorphisms Alter Thiopurine Metabolism and Hematopoietic Toxicity

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          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.

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          Most cited references 44

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          Nucleoside analogues have been in clinical use for almost 50 years and have become cornerstones of treatment for patients with cancer or viral infections. The approval of several additional drugs over the past decade demonstrates that this family still possesses strong potential. Here, we review new nucleoside analogues and associated compounds that are currently in preclinical or clinical development for the treatment of cancer and viral infections, and that aim to provide increased response rates and reduced side effects. We also highlight the different approaches used in the development of these drugs and the potential of personalized therapy.
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            Biology, risk stratification, and therapy of pediatric acute leukemias: an update.

            We review recent advances in the biologic understanding and treatment of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), identify therapeutically challenging subgroups, and suggest future directions of research. A review of English literature on childhood acute leukemias from the past 5 years was performed. Contemporary treatments have resulted in 5-year event-free survival rates of approximately 80% for childhood ALL and almost 60% for pediatric AML. The advent of high-resolution genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Virtually all ALL and the vast majority of AML cases can be classified according to specific genetic abnormalities. Cooperative mutations involved in cell differentiation, cell cycle regulation, tumor suppression, drug responsiveness, and apoptosis have also been identified in many cases. The development of new formulations of existing drugs, molecularly targeted therapy, and immunotherapies promises to further advance the cure rates and improve quality of life of patients. The application of new high-throughput sequencing techniques to define the complete DNA sequence of leukemia and host normal cells and the development of new agents targeted to leukemogenic pathways promise to further improve outcome in the coming decade.
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              Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing.

              Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                14 September 2016
                15 February 2016
                April 2016
                01 October 2016
                : 48
                : 4
                : 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: (901)595-2517
                [*]

                These authors contributed equally

                Article
                PMC5029084 PMC5029084 5029084 nihpa813033
                10.1038/ng.3508
                5029084
                26878724
                Categories
                Article

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