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We initially focused on profiles associated with overexpression of the adverse metabolic marker glycosyltransferase (UGT2B17) associated with poor survival and drug resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Leukaemic B\u2010cell metabolomes indicated a significant perturbation in lipids, predominantly bio\u2010active sphingolipids. Expression of numerous enzyme\u2010encoding genes of sphingolipid biosynthesis pathways was significantly associated with shorter patient survival. Targeted metabolomics further exposed higher circulating levels of glucosylceramides (C16:0 GluCer) in CLL patients relative to healthy donors and an aggressive cancer biology. In multivariate analyses, C16:0 GluCer and sphinganine were independent prognostic markers and were inversely linked to treatment\u2010free survival. These two sphingolipid species function as antagonistic mediators, with sphinganine being pro\u2010apoptotic and GluCer being pro\u2010proliferative, tested in leukemic B\u2010CLL cell models. Blocking GluCer synthesis using ceramide glucosyltransferase inhibitors induced cell death and reduced the proliferative phenotype, which further sensitized a leukaemic B\u2010cell model to the anti\u2010leukaemics fludarabine and ibrutinib in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Specific sphingolipids may serve as prognostic markers in CLL, and inhibiting enzymatic pathways involved in their biosynthesis has potential as a therapaeutic approach.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1442","type":"journal-article","created":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T06:49:17Z","timestamp":1701413357000},"source":"Crossref","is-referenced-by-count":11,"title":["Untargeted metabolomics identifies metabolic dysregulation of sphingolipids associated with aggressive chronic lymphocytic leukaemia and poor survival"],"prefix":"10.1002","volume":"13","author":[{"given":"Flora","family":"Nguyen Van 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