<i>NUDT15</i> Polymorphisms Alter Thiopurine Metabolism and Hematopoietic Toxicity

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

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.

Related collections

Most cited references 44

Record: found
Abstract: found
Article: not found

Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases.

Lars Petter Jordheim, David Durantel, Fabien Zoulim … (2013)

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.

0 comments Cited 303 times – based on 0 reviews      Review now

Record: found
Abstract: found
Article: not found

Biology, risk stratification, and therapy of pediatric acute leukemias: an update.

Ching-Hon Pui, William Carroll, Soheil Meshinchi … (2011)

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.

0 comments Cited 256 times – based on 0 reviews      Review now

Record: found
Abstract: found
Article: not found

Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.

N Goulden, Chris Mitchell, Rachel Wade … (2013)

Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification. Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119. Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42-72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5%, 92·8-98·2; unadjusted odds ratio 1·00, 95% CI 0·43-2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI -5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3-8·9) given one delayed intensification and six (2·4%, 0·2-4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0-2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one (<1%) treatment-related death, and 74 episodes of grade 3 or 4 toxic effects in 45 patients (17%). Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy. Medical Research Council and Leukaemia and Lymphoma Research. Copyright © 2013 Elsevier Ltd. All rights reserved.

0 comments Cited 163 times – based on 0 reviews      Review now

All references

Author and article information

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: (901)595-2517

[*]

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

SO-VID: 43a7df4c-1bc4-4e83-8e3d-39bd796b7c90

History

Comments

Comment on this article

Cited by 178

See all cited by

Most referenced authors 692

See all reference authors

NUDT15 Polymorphisms Alter Thiopurine Metabolism and Hematopoietic Toxicity

Read this article at