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Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia

The Pharmacogenomics Journal volume 18, pages 275–280 (2018)Cite this article

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Abstract

6-Mercaptopurine (6-MP) is a main component of childhood acute lymphoblastic leukemia (ALL) treatment. Some candidate gene variants are associated with its toxicities, but the major variants and effects of combined variants remain unclear. We used Cox regression analysis to evaluate the time-dependent association between candidate variants and the cumulative incidence of 6-MP intolerability in 95 Japanese patients. The major risk factors for severe leukopenia were ABCC4 rs3765534, NUDT15 rs116855232 and rs186364861 in multi-covariate analysis (P<0.05). NUDT15 intermediate activity variant, that is, heterozygous rs116855232 or rs186364861 variant, and the ABCC4 rs3765534 variant showed leukopenia more frequently than either variant alone. All patients with both the intermediate activity NUDT15 variant and the ABCC4 rs3765534 variant suffered from leukopenia, and 57.1% patients required 50% protocol dose by day 168. These data indicate that NUDT15 and ABCC4 are major factors for 6-MP intolerability and that the interaction between these variants enhances intolerability to 6-MP.

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Acknowledgements

This work was supported by JSPS KAKENHI (Grant No. 15K18932). We thank Enago for the English language review.

Author contributions

YT and AM designed the experiments. YT analyzed and wrote the paper. HN, K Kondoh, KN and K Koh collected the data.

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Authors and Affiliations

  1. Department of Clinical Pharmacy, School of Pharmacy, Kitasato University, Tokyo, Japan

    Y Tanaka

  2. Department of General Pediatrics & Interdisciplinary Medicine, National Center for Child Health and Development, Tokyo, Japan

    H Nakadate

  3. Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan

    K Kondoh

  4. Department of Pediatrics, Teikyo University Hospital, Tokyo, Japan

    K Nakamura

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

    K Koh

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

    A Manabe

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  1. Y Tanaka
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  4. K Nakamura
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  5. K Koh
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Correspondence to Y Tanaka.

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Tanaka, Y., Nakadate, H., Kondoh, K. et al. Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia. Pharmacogenomics J 18, 275–280 (2018). https://doi.org/10.1038/tpj.2017.12

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