The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia.
The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia.
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DOI：
10.1097/fpc.0000000000000282
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发表时间：
2017-06
影响因子：
2.6
通讯作者：
Hori H
中科院分区：
文献类型：
--
作者：
Moriyama T;Nishii R;Lin TN;Kihira K;Toyoda H;Jacob N;Kato M;Koh K;Inaba H;Manabe A;Schmiegelow K;Yang JJ;Hori H
硫嘌呤（例如，巯基嘌呤[MP]）是广泛用于治疗具有剂量限制性造血毒性的小儿急性淋巴细胞白血病（ALL）的化疗剂。最近，NUDT 15的生殖系变异已被确定为MP相关骨髓抑制的主要遗传原因，并且对NUDT 15基因型指导的MP剂量个体化的临床实施越来越感兴趣。因此，我们试图评估NUDT 15对巯基嘌呤代谢的影响，并鉴定药理学标志物以告知NUDT 15基因型指导的MP给药。在55例日本ALL患儿中，我们同时测定了红细胞中的硫鸟嘌呤核苷酸（TGN）和白色细胞中的DNA掺入硫鸟嘌呤（DNA-TG）。NUDT 15缺陷患者的TGN水平显著较低，可能是由于毒性相关的MP剂量减少。相比之下，当暴露于相同剂量的MP时，DNA-TG在NUDT 15中随着风险等位基因数量的增加而在体内更有效地积累（P = 4.0 × 10−9）。细胞质TGN和细胞核DNA-TG在各基因型组之间呈正相关（P = 6.5 × 10−4），但NUDT 15缺陷患者的DNA-TG与TGN的比值显著更高（P = 3.6 × 10−9），与MP过度激活一致。总之，我们的研究结果表明，DNA-TG是一个更相关的MP代谢物比TGN通知NUDT 15基因型指导的剂量调整。
Thiopurines (e.g., mercaptopurine [MP]) are widely used chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia (ALL) 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 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 ALL, 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 due to 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 positively correlated 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.