{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNT5C2 encodes cytosolic 5′‑nucleotidase II, a key enzyme that dephosphorylates purine nucleoside monophosphates (such as IMP and GMP) to regulate intracellular nucleotide pools. In hematological malignancies, particularly acute lymphoblastic leukemia (ALL), activating somatic mutations in NT5C2 have been shown to dramatically enhance its enzymatic activity, thereby accelerating the inactivation of nucleoside analog pro‐drugs (e.g., 6‑mercaptopurine and 6‑thioguanine). This hyperactivation drives chemotherapy resistance and clonal relapse by effectively reducing the intracellular accumulation of the active thiopurine metabolites that are needed for cytotoxicity. Studies using whole‑exome and transcriptome sequencing in relapsed ALL have demonstrated that both clonal and subclonal NT5C2 mutations confer drug resistance, correlate with early relapse, and alter metabolomic profiles, highlighting NT5C2’s pivotal role as a mediator of acquired resistance in leukemias."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its pathological activation in drug‐resistant leukemia, NT5C2’s biochemical and structural properties underline its central regulatory function in nucleotide metabolism. High‐resolution structural studies have revealed that NT5C2 operates under tight allosteric control by adenine-based nucleotides and other phosphate-containing metabolites, which induce conformational changes in its catalytic and regulatory centers. Furthermore, protein–protein interaction studies indicate that NT5C2 may engage in complexes (for example, via its interaction with leucine rich repeat domains of other proteins) that could modulate its activity and, consequently, impact nucleoside analogue activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in chemotherapy resistance, NT5C2 has emerged as a candidate gene in several genome‑wide association studies and functional analyses of metabolic and neuropsychiatric disorders. Variants near or within NT5C2 have been associated with body mass index and obesity in Asian cohorts, suggesting that altered NT5C2 activity might influence energy metabolism. In the central nervous system, NT5C2 expression differences—sometimes modulated by regulatory variants that affect miRNA binding—have been linked to schizophrenia risk, and rare missense mutations in NT5C2 have been implicated in neurodegenerative phenotypes such as hereditary spastic paraplegia. Moreover, experimental deletion of NT5C2 in animal models has been reported to confer protection against high‑fat diet–induced weight gain and metabolic derangements, and epigenetic down‑regulation of NT5C2 has been connected with impaired insulin receptor expression in type 2 diabetes, while polymorphisms have also been tied to coronary heart disease susceptibility. These diverse genetic and metabolic associations underscore the enzyme’s broad impact on cellular homeostasis and disease susceptibility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Gannie Tzoneva, Arianne Perez-Garcia, Zachary Carpenter, et al. 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