Preclinical evaluation of NUDT15-guided thiopurine therapy and its effects on toxicity and antileukemic efficacy

Author:

Nishii Rina12,Moriyama Takaya1ORCID,Janke Laura J.3,Yang Wenjian1,Suiter Chase C.1ORCID,Lin Ting-Nien1,Li Lie1,Kihira Kentaro4,Toyoda Hidemi4,Hofmann Ute56,Schwab Matthias5678,Takagi Masatoshi2,Morio Tomohiro2,Manabe Atsushi9,Kham Shirley1011,Jiang Nan1011,Rabin Karen R.12,Kato Motohiro13,Koh Katsuyoshi14,Yeoh Allen Eng-Juh101115,Hori Hiroki4,Yang Jun J.11617ORCID

Affiliation:

1. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN;

2. Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan;

3. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN;

4. Department of Pediatrics, Graduate School of Medicine, Mie University, Mie, Japan;

5. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany;

6. Department of Clinical Pharmacology, University of Tuebingen, Stuttgart, Germany;

7. Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany;

8. Department of Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany;

9. St. Luke’s International Hospital, Tokyo, Japan;

10. Khoo Teck Puat–National University Children’s Medical Institute, National University Hospital, National University Health System, Singapore;

11. VIVA-NUS Center for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, Singapore;

12. Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX;

13. Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan;

14. Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan;

15. Cancer Science Institute of Singapore, National University of Singapore, Singapore; and

16. Department of Oncology and

17. Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children’s Research Hospital, Memphis, TN

Abstract

Key Points We established a Nudt15 knockout mouse model with which to evaluate individualized thiopurine therapy. Preemptive NUDT15 genotype–guided thiopurine dosing can effectively prevent drug toxicity without compromising antileukemic efficacy.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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