Metabolomics Unveiled the Potential Role of N1-Acetylspermidine As a Biomarker in T-Lymphoblastic Lymphoma/Leukemia Monitoring

Objective: For adult patients with T lymphoblastic leukemia/lymphoma (T-ALL/LBL), current methods for therapeutic response monitoring based on bone marrow examinations lack convenience. A biomarker in blood with high sensitivity can make daily monitoring easier. Our team attempted to identify easily obtained and highly sensitive T-ALL/LBL tumor biomarkers through metabolomics, and meanwhile explore potential metabolic therapeutic targets.

Methods: We performed non-targeted metabolomic analysis on archived plasma samples from 30 newly diagnosed T-ALL/LBL patients and matched controls from 2015-2018. Based on these results, we expanded the sample size to 50 patient and matched control plasmas for targeted metabolomic validation, and explored potential mechanisms using public databases.

Results: A total of 90 differential compounds were detected in non-targeted analysis. Orthogonal partial least squares discriminant analysis showed that the metabolic patterns of the patients and the controls were significantly different (R2=0.915, Q2=0.723, pR2=0.010, PQ2=0.010). KEGG pathway enrichment showed that the detected differential compounds were involved in 41 known metabolic pathways, and the methionine metabolism pathway was highly ranked. Random forest analysis verified significant differentiation between cases and controls based on metabolic differences (ROC curve AUC=0.928, p<0.001), with acetylspermidine contributing most significantly. Targeted validation in the expanded cohort showed decreased methionine, increased methylthioadenosine, and significantly increased N1-acetylspermidine in patient plasma. All these three metabolites could be localized in methionine and related polyamine metabolism pathways, with N1-acetylspermidine upregulation particularly pronounced (fold change=3.590, p<0.001). Plasma N1-acetylspermidine alone could effectively differentiate patients from controls (ROC curve AUC=0.888, p<0.001). Public database records (GSE109231) suggested that upregulated spermidine synthase may explain this alteration in N1-acetylspermidine.

Conclusion: N1-Acetylspermidine showed promising potential as a tumor biomarker for T-ALL/LBL therapeutic monitoring, while methionine and polyamine metabolism abnormalities may constitute new T-ALL/LBL metabolic therapeutic targets.