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

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 - Nersting, Jacob

AU - Kato, Motohiro

AU - Koh, Katsuyoshi

AU - Inaba, Hiroto

AU - Manabe, Atsushi

AU - Schmiegelow, Kjeld

AU - Yang, Jun J.

AU - Hori, Hiroki

PY - 2017

Y1 - 2017

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=4.0×10-9). Cytosolic TGN and nuclear DNA-TG were correlated positively with each other across genotype groups (P=6.5×10-4), but the ratio of DNA-TG to TGN was significantly higher in NUDT15-deficient patients (P=3.6×10-9), 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=4.0×10-9). Cytosolic TGN and nuclear DNA-TG were correlated positively with each other across genotype groups (P=6.5×10-4), but the ratio of DNA-TG to TGN was significantly higher in NUDT15-deficient patients (P=3.6×10-9), 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 - 6-Thiopurine

KW - acute lymphoblastic leukemia

KW - DNA-TG

KW - individualized therapy

KW - NUDT15

U2 - 10.1097/FPC.0000000000000282

DO - 10.1097/FPC.0000000000000282

M3 - Journal article

C2 - 28445187

AN - SCOPUS:85018252952

SN - 1744-6872

VL - 27

SP - 236

EP - 239

JO - Pharmacogenetics

JF - Pharmacogenetics

IS - 6

ER -