急性淋巴细胞白血病的药物遗传学：综合进展以实现个体化硫嘌呤治疗
{"_":" Pharmacogenetics in Acute Lymphoblastic Leukemia: Synthesizing Progress for Personalized Thiopurine Therapy.","i":["NUDT15"]}
摘要(中文译文)
急性淋巴细胞白血病（ALL）是最常见的儿童恶性肿瘤，其治疗在维持阶段高度依赖硫嘌呤类药物，如6-巯基嘌呤（6-MP）。然而，显著的个体间反应差异和高风险的骨髓抑制常常影响治疗效果。药物遗传学为个体化治疗提供了关键策略。虽然硫嘌呤甲基转移酶（TPMT）最初是主要关注焦点，但NUDT15的发现似乎是硫嘌呤不耐受的更全面决定因素。本综述旨在整合并批判性评估在揭示NUDT15药物遗传学在硫嘌呤治疗中的生物学机制和临床意义方面所取得的进展。基础研究表明，NUDT15在活性硫嘌呤的解毒过程中发挥重要作用，常见遗传变异（例如p.Arg139Cys）显著破坏其活性，导致毒性代谢物蓄积。观察性研究一致地将NUDT15变异与严重骨髓抑制相关联，尤其是在亚洲人群中。近期随机对照试验（RCT）证实，NUDT15基因型指导的给药可有效降低硫嘌呤诱导的毒性，且不干扰治疗结局。尽管取得了这些进展，挑战仍然存在，包括罕见变异特征描述不完整、亚洲多样化人群数据有限，以及需要与代谢物监测进行标准化整合。总之，NUDT15药物遗传学对于提高ALL治疗中的患者安全性和优化硫嘌呤剂量至关重要。为使硫嘌呤个体化治疗得到广泛且公平的实施，未来研究应侧重于增加不同人群的遗传数据、改进剂量调整算法，并统一治疗指南。
Abstract
The management of acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, critically relies on thiopurine therapy, such as 6-mercaptopurine (6-MP), during the maintenance phase. However, significant inter-individual response variety and high risk of myelosuppression often disrupt therapy efficacy. Pharmacogenetics offer crucial strategies to personalized therapy. While thiopurine methyltransferase () was initially the primary focus, the discovery of () appears as a more comprehensive determinant of thiopurine intolerance. This review aims to consolidate and critically evaluate the advancement achieved in unraveling the biological mechanism and clinical significance of pharmacogenetics in thiopurine therapy. Foundational studies showed the vital role of in the detoxification of active thiopurines, with common genetic variants (for instance, p. Arg139Cys) significantly disrupting its activity, leading to the accumulation of toxic metabolites. Observational studies consistently associated variants with severe myelosuppression, notably in Asian populations. Recent randomized controlled trials (RCTs) confirmed that genotype-guided dosing effectively reduces thiopurine-induced toxicity without interfering with the therapeutic outcome. Despite these advancements, challenges remain present, including the incomplete characterization of rare variants, limited data in the diverse Asian populations, and the need for standardized integration with metabolite monitoring. In conclusion, pharmacogenetics is essential for improving patient safety and thiopurine dosage optimization in the treatment of ALL. For thiopurine tailored medicine to be widely and fairly implemented, future research should focus on increasing genetic data across different populations, improving the dose adjustment algorithm, and harmonizing therapeutic guidelines.
如何引用
AMA
Isfahan Shah Lubis, Kusnandar Anggadiredja, Aluicia Anita Artarini, Nur Melani Sari, Nur Suryawan, Zulfan Zazuli. {"_":" Pharmacogenetics in Acute Lymphoblastic Leukemia: Synthesizing Progress for Personalized Thiopurine Therapy.","i":["NUDT15"]}. Medical sciences (Basel, Switzerland). 2025; doi:10.3390/medsci13030112.
APA
Isfahan Shah Lubis, Kusnandar Anggadiredja, Aluicia Anita Artarini, Nur Melani Sari, Nur Suryawan, Zulfan Zazuli (2025). {"_":" Pharmacogenetics in Acute Lymphoblastic Leukemia: Synthesizing Progress for Personalized Thiopurine Therapy.","i":["NUDT15"]}. Medical sciences (Basel, Switzerland). https://doi.org/10.3390/medsci13030112
GB/T 7714
Isfahan Shah Lubis, Kusnandar Anggadiredja, Aluicia Anita Artarini, Nur Melani Sari, Nur Suryawan, Zulfan Zazuli. {"_":" Pharmacogenetics in Acute Lymphoblastic Leukemia: Synthesizing Progress for Personalized Thiopurine Therapy.","i":["NUDT15"]}[J]. Medical sciences (Basel, Switzerland), 2025 doi:10.3390/medsci13030112.
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