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The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia

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Harvard

Moriyama, T, Nishii, R, Lin, T-N, Kihira, K, Toyoda, H, Jacob, N, Kato, M, Koh, K, Inaba, H, Manabe, A, Schmiegelow, K, Yang, JJ & Hori, H 2017, 'The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia', Pharmacogenetics and Genomics, bind 27, nr. 6, s. 236-239. https://doi.org/10.1097/FPC.0000000000000282

APA

Moriyama, T., Nishii, R., Lin, T-N., Kihira, K., Toyoda, H., Jacob, N., Kato, M., Koh, K., Inaba, H., Manabe, A., Schmiegelow, K., Yang, J. J., & Hori, H. (2017). The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia. Pharmacogenetics and Genomics, 27(6), 236-239. https://doi.org/10.1097/FPC.0000000000000282

CBE

MLA

Vancouver

Author

Moriyama, Takaya ; Nishii, Rina ; Lin, Ting-Nien ; Kihira, Kentaro ; Toyoda, Hidemi ; Jacob, Nersting ; Kato, Motohiro ; Koh, Katsuyoshi ; Inaba, Hiroto ; Manabe, Atsushi ; Schmiegelow, Kjeld ; Yang, Jun J ; Hori, Hiroki. / The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia. I: Pharmacogenetics and Genomics. 2017 ; Bind 27, Nr. 6. s. 236-239.

Bibtex

@article{010ffaf2d2844fcba0b832e0b701cc6c,
title = "The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia",
abstract = "Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in the clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing. In 55 Japanese children with acute lymphoblastic leukemia, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely because of toxicity-related MP dose reduction. In contrast, when exposed to the same dose of MP, DNA-TG accumulated more efficiently in vivo with increasing number of risk alleles in NUDT15 (P=4.0×10). Cytosolic TGN and nuclear DNA-TG were correlated positively with each other across genotype groups (P=6.5×10), but the ratio of DNA-TG to TGN was significantly higher in NUDT15-deficient patients (P=3.6×10), consistent with excessive MP activation. In conclusion, our results suggest that DNA-TG is a more relevant MP metabolite than TGN to inform NUDT15 genotype-guided dose adjustments.",
keywords = "Journal Article",
author = "Takaya Moriyama and Rina Nishii and Ting-Nien Lin and Kentaro Kihira and Hidemi Toyoda and Nersting Jacob and Motohiro Kato and Katsuyoshi Koh and Hiroto Inaba and Atsushi Manabe and Kjeld Schmiegelow and Yang, {Jun J} and Hiroki Hori",
year = "2017",
month = jun,
doi = "10.1097/FPC.0000000000000282",
language = "English",
volume = "27",
pages = "236--239",
journal = "Pharmacogenetics and Genomics",
issn = "1744-6872",
publisher = "Lippincott Williams & Wilkins",
number = "6",

}

RIS

TY - JOUR

T1 - The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia

AU - Moriyama, Takaya

AU - Nishii, Rina

AU - Lin, Ting-Nien

AU - Kihira, Kentaro

AU - Toyoda, Hidemi

AU - Jacob, Nersting

AU - Kato, Motohiro

AU - Koh, Katsuyoshi

AU - Inaba, Hiroto

AU - Manabe, Atsushi

AU - Schmiegelow, Kjeld

AU - Yang, Jun J

AU - Hori, Hiroki

PY - 2017/6

Y1 - 2017/6

N2 - Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in the clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing. In 55 Japanese children with acute lymphoblastic leukemia, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely because of toxicity-related MP dose reduction. In contrast, when exposed to the same dose of MP, DNA-TG accumulated more efficiently in vivo with increasing number of risk alleles in NUDT15 (P=4.0×10). Cytosolic TGN and nuclear DNA-TG were correlated positively with each other across genotype groups (P=6.5×10), but the ratio of DNA-TG to TGN was significantly higher in NUDT15-deficient patients (P=3.6×10), consistent with excessive MP activation. In conclusion, our results suggest that DNA-TG is a more relevant MP metabolite than TGN to inform NUDT15 genotype-guided dose adjustments.

AB - Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in the clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing. In 55 Japanese children with acute lymphoblastic leukemia, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely because of toxicity-related MP dose reduction. In contrast, when exposed to the same dose of MP, DNA-TG accumulated more efficiently in vivo with increasing number of risk alleles in NUDT15 (P=4.0×10). Cytosolic TGN and nuclear DNA-TG were correlated positively with each other across genotype groups (P=6.5×10), but the ratio of DNA-TG to TGN was significantly higher in NUDT15-deficient patients (P=3.6×10), consistent with excessive MP activation. In conclusion, our results suggest that DNA-TG is a more relevant MP metabolite than TGN to inform NUDT15 genotype-guided dose adjustments.

KW - Journal Article

U2 - 10.1097/FPC.0000000000000282

DO - 10.1097/FPC.0000000000000282

M3 - Journal article

C2 - 28445187

VL - 27

SP - 236

EP - 239

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

SN - 1744-6872

IS - 6

ER -

ID: 52772900