DNA polymerase gamma variants and hepatotoxicity during maintenance therapy of childhood acute lymphoblastic leukemia: is there a causal relationship?

IF 2.9 3区 医学 Q2 GENETICS & HEREDITY Pharmacogenomics Journal Pub Date : 2023-05-03 DOI:10.1038/s41397-023-00303-0
Tekla Harju, Anri Hurme-Niiranen, Maria Suo-Palosaari, Stine Nygaard Nielsen, Reetta Hinttala, Kjeld Schmiegelow, Johanna Uusimaa, Arja Harila, Riitta Niinimäki
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Abstract

Hepatotoxicity is a frequent complication during maintenance therapy of acute lymphoblastic leukemia (ALL) with 6-mercaptopurine and methotrexate. Elevated levels of methylated 6-mercaptopurine metabolites (MeMP) are associated with hepatotoxicity. However, not all mechanisms are known that lead to liver failure in patients with ALL. Variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma (POLG1), have been related to drug-induced hepatotoxicity, for example, by sodium valproate. The association of common POLG variants with hepatotoxicity during maintenance therapy was studied in 34 patients with childhood ALL. Of the screened POLG variants, four different variants were detected in 12 patients. One patient developed severe hepatotoxicity without elevated MeMP levels and harbored a heterozygous POLG p.G517V variant, which was not found in the other patients.

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DNA聚合酶γ变体与儿童急性淋巴细胞白血病维持治疗期间的肝毒性:是否存在因果关系?
肝毒性是用6-巯基嘌呤和甲氨蝶呤维持治疗急性淋巴细胞白血病(ALL)的常见并发症。甲基化6-巯基嘌呤代谢产物(MeMP)水平升高与肝毒性有关。然而,并非所有导致all患者肝功能衰竭的机制都是已知的。POLG基因编码线粒体DNA聚合酶γ(POLG1)的催化亚基,其变体与药物诱导的肝毒性有关,例如丙戊酸钠。研究了34例儿童ALL患者在维持治疗期间常见POLG变异与肝毒性的关系。在筛选的POLG变体中,在12名患者中检测到4种不同的变体。一名患者在MeMP水平未升高的情况下出现严重肝毒性,并携带杂合子POLG p.G517V变体,而在其他患者中未发现该变体。
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来源期刊
Pharmacogenomics Journal
Pharmacogenomics Journal 医学-药学
CiteScore
7.20
自引率
0.00%
发文量
35
审稿时长
6-12 weeks
期刊介绍: The Pharmacogenomics Journal is a print and electronic journal, which is dedicated to the rapid publication of original research on pharmacogenomics and its clinical applications. Key areas of coverage include: Personalized medicine Effects of genetic variability on drug toxicity and efficacy Identification and functional characterization of polymorphisms relevant to drug action Pharmacodynamic and pharmacokinetic variations and drug efficacy Integration of new developments in the genome project and proteomics into clinical medicine, pharmacology, and therapeutics Clinical applications of genomic science Identification of novel genomic targets for drug development Potential benefits of pharmacogenomics.
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