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Acute lymphoblastic leukemia

Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms

Leukemia volume 32, pages 2710–2714 (2018)Cite this article

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Thiopurines are key to the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in children and adults, and 6-mercaptopurine (6-MP) is commonly used in consolidation and maintenance therapy [1,2,3]. Leukopenia is a dose-limiting toxicity of 6-MP partly explained by hypomorphic variants of TPMT [2,3,4,5] and clinical importance of TMPT genotyping is well established. Recently, NUDT15 was identified as a novel thiopurine regulator conferring 6-MP sensitivity most prominently in Asians and Hispanics [4,5,6,7,8,9]. Patients with bi-allelic NUDT15 variants are extremely sensitive to 6-MP, and only 5–10% of the standard dose is sufficient to maintain the target leukocyte count [4, 8].

However, a convenient method to determine the diplotype of NUDT15 has not been established, and as shown in the previous study, the diplotype is currently inferred using a public catalog of human variants [4]. Herein we demonstrated a method for identifying the diplotype using droplet digital PCR (ddPCR), and confirmed the results by wild-type specific PCR by a restriction enzyme.

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Acknowledgements

The authors would like to thank Ms. Natsuko Ariizumi, Ms. Shinobu Kobayashi, and Ms. Yoshie Fukumasa for their technical assistance. We also thank Mr. Yukinori Yatsuda (Bio-rad) for his assistance with the ddPCR analysis. The authors thank Mr. James R. Valera of the Department of Education for Clinical Research of the National Center for Child Health and Development for his assistance in proofreading and editing this manuscript. This study was supported in part by the Japan Society for the Promotion of Science (JSPS) through a Grant-in-Aid for Scientific Research (KAKENHI, grant number 17H04234), by a grant from the National Center for Child Health and Development (grant numbers 28-5), by grant 17km0405107h0005, 17ck0106253h0001, and 17ck0106219h0002 from the Japan Agency for Medical Research and development, (AMED), and by foundation for National Institutes of Health (GM118578, GM115279, and P30CA21765) and the V Foundation for Cancer Research (T2015-006). T.M is supported by the Garwood Fellowship at St. Jude Children’s Research Hospital.

Author contributions

MK is the principal investigator and takes primary responsibility for the paper, designed this study, interpreted data, wrote the manuscript, and gave final approval; ST, TO collected data, analyzed data, interpreted data, and wrote the manuscript; TO evaluated patients, collected data, analyzed data, interpreted data, and wrote the manuscript; MU, RS, TM, RN, YY, TU, NK and JJY collected data, analyzed data, interpreted data. KK, MS, YA, KT, SI, KK, JT, EI and DT evaluated patients, and collected data; All authors discussed the results and critically reviewed the manuscript.

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Author notes

  1. These authors contributed equally: Shinichi Tsujimoto, Tomoo Osumi.

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan

    Shinichi Tsujimoto, Tomoo Osumi, Meri Uchiyama, Ryota Shirai, Masanori Yoshida, Nobutaka Kiyokawa & Motohiro Kato

  2. Department of Pediatrics, Yokohama City University, Yokohama, Japan

    Shinichi Tsujimoto & Shuichi Ito

  3. Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan

    Tomoo Osumi, Yuji Yamada, Daisuke Tomizawa & Motohiro Kato

  4. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA

    Takaya Moriyama, Rina Nishii & Jun J. Yang

  5. Department of Pediatrics, Hirosaki University, Hirosaki, Japan

    Ko Kudo, Kiminori Terui & Etsuro Ito

  6. Department of Pediatrics, University of Tokyo, Tokyo, Japan

    Masahiro Sekiguchi & Junko Takita

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

    Yuki Arakawa & Katsuyoshi Koh

  8. Department of Human Genetics, National Research Institute for Child Health and Development, Tokyo, Japan

    Toru Uchiyama

  9. Department of Pediatrics, St. Luke’s International Hospital, Tokyo, Japan

    Atsushi Manabe

  10. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA

    Jun J. Yang

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  1. Shinichi Tsujimoto
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Correspondence to Motohiro Kato.

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Tsujimoto, S., Osumi, T., Uchiyama, M. et al. Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms. Leukemia 32, 2710–2714 (2018). https://doi.org/10.1038/s41375-018-0190-1

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