Kager Leo, Boztug Kaan
St. Anna Children's Hospital, Vienna, Austria.
Medical University of Vienna, Department of Pediatrics and Adolescent Medicine, Vienna, Austria.
J Clin Invest. 2025 Jul 15;135(14). doi: 10.1172/JCI194434.
Purine nucleotides are critical for nucleic acid synthesis, signaling, and cellular metabolism. Thiopurines (TPs), including 6-mercaptopurine and 6-thioguanine, are cornerstone agents for the treatment of acute lymphoblastic leukemia (ALL). TP efficacy and cytotoxicity depend on the metabolism and intracellular activation of TPs, a process influenced by pharmacogenes such as thiopurine-S methyltransferase (TPMT) and NUDIX (nucleoside diphosphates linked to moiety-X) hydrolase 15 (NUDT15). In this issue of the JCI, Maillard et al. identified NUDT5 as a determinant of TP pharmacology. They demonstrated that loss of NUDT5 conferred TP resistance by impairing drug activation and DNA damage responses. Metabolomics studies by Maillard and others revealed that NUDT5 may regulate the balance between the de novo purine synthesis and salvage pathways. Clinically, NUDT5 expression variants were associated with altered TP tolerance. These findings position NUDT5 as a key modulator of nucleotide metabolism and TP efficacy, with potential implications for pharmacogenomics-guided therapy optimization in ALL.
嘌呤核苷酸对于核酸合成、信号传导和细胞代谢至关重要。硫嘌呤（TPs），包括6-巯基嘌呤和6-硫鸟嘌呤，是治疗急性淋巴细胞白血病（ALL）的基石药物。TP的疗效和细胞毒性取决于TP的代谢和细胞内激活，这一过程受硫嘌呤-S甲基转移酶（TPMT）和NUDIX（与X部分相连的核苷二磷酸）水解酶15（NUDT15）等药物基因的影响。在本期《临床研究杂志》中，Maillard等人确定NUDT5是TP药理学的一个决定因素。他们证明，NUDT5的缺失通过损害药物激活和DNA损伤反应导致TP耐药。Maillard等人的代谢组学研究表明，NUDT5可能调节从头嘌呤合成和补救途径之间的平衡。临床上，NUDT5表达变异与TP耐受性改变有关。这些发现将NUDT5定位为核苷酸代谢和TP疗效的关键调节因子，对ALL中药物基因组学指导的治疗优化具有潜在意义。
