ArticleMolecular biomedicine2025
A single non-coding SNP in FPGS modulates folate drug efficacy in acute lymphoblastic leukemia: data-driven exploration and experimental validation.
Article in Molecular biomedicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
1 citing paper in PubMed, 1 synthesis or guideline pooled it.
- Association of folylpolyglutamate synthase polymorphisms with methotrexate response and toxicity in rheumatoid arthritis: a meta-analysis.The pharmacogenomics journal · 2026Pooled it
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Authors and funding
12 authors.
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Abstract
For over 70 years, methotrexate (MTX) has remained a first-line chemotherapeutic agent for acute lymphoblastic leukemia (ALL), playing a pivotal role in maintenance therapy. Understanding the genetic determinants of MTX efficacy is therefore essential for improving clinical outcomes. However, studies on MTX efficacy-related polymorphisms remain limited, particularly for non-coding variants, for which most evidence is based on statistical associations. Here, through integrative bioinformatics analysis and systematic meta-analysis, we identified rs1544105, a non-coding SNP in the folylpoly-γ-glutamate synthetase (FPGS) gene, as closely associated with MTX efficacy. Compared with the GG genotype, the AA genotype increased disease progression risk (OR: 2.23; 95% CI: 1.16-4.30; p = 0.017) and elevated plasma MTX concentration-to-dose ratios at 24 h (WMD: 2.27; 95% CI: 1.04-4.40; p = 0.002) and 40 h (WMC: 0.02; 95% CI: 0.00-0.04; p = 0.033). Using prime editing, we generated homozygous mutant (GG) 293T cells, demonstrating that rs1544105 A > G increased FPGS expression (~ 1.5-fold, p < 0.05) and intracellular MTX retention (p < 0.05). Moreover, both cell-based and animal experiments confirmed that rs1544105 A > G markedly improved MTX efficacy. Mechanistically, dual-luciferase reporter and electrophoretic mobility shift assays revealed that rs1544105 A > G enhanced the binding affinity of the SNP-containing sequence for the transcription factor CREB1, thereby increasing FPGS transcriptional activity and ultimately augmenting MTX efficacy. Our multidimensional study, integrating data analysis with cellular, molecular, and animal experiments, highlights the remarkable regulatory role of a single SNP, rs1544105, in modulating MTX therapeutic response and provides a basis for individualized MTX-based maintenance therapy in ALL patients.
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