Clinico-Metabolic Profiling Unraveled Key Metabolic Alterations Underlying the Pathophysiology of Chronic Myeloid...

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm. Despite the success of tyrosine kinase inhibitors, therapeutic resistance and disease progression remain significant challenges. This highlights the need for novel biomarkers to facilitate early diagnosis, deepen our understanding of the disease, and pave the way for new therapeutic approaches. This study analyzed serum metabolic profiles of 30 newly diagnosed treatment-naive CML patients and 20 age- and sex-matched healthy controls using ¹H nuclear magnetic resonance (NMR) spectroscopy, followed by multivariate and univariate statistical approaches. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analysis. Thirty-eight metabolites were identified, and multivariate analysis revealed significant metabolic disparity between CML and control subjects with substantial alterations in amino acid and energy metabolism. Key eight metabolites, including histidine, alanine, valine, glutamine, tyrosine, serine, glucose, and isoleucine, demonstrated consistent downregulation in CML, reflecting enhanced cellular uptake and metabolic rewiring characteristic of leukemic proliferation. Depletion of branched-chain amino acids and increased reliance on glutamine and glycolytic intermediates highlight vulnerabilities that may be exploited for therapeutic intervention. ROC analysis demonstrated promising discriminatory ability of these metabolites in this cohort, with several achieving an area under the ROC curve (AUROC) > 0.90, suggesting their potential as biomarkers in this cohort their utility . Serum metabolomics reveals a distinct CML signature marked by enhanced bioenergetic and biosynthetic demands, immune evasion, and drug resistance mechanisms. These findings underscore the potential of serum metabolic profiles as noninvasive biomarkers at the exploratory discovery stage, while also providing preliminary pathophysiological insights that may guide future studies on metabolism-targeted therapeutic strategies.