Identification of Metabolic Biomarkers in Bone Marrow Aspirate for Diagnosis, Prognosis, and Therapeutic Monitoring in Pediatric Langerhans Cell Histiocytosis.
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BACKGROUND: Metabolic reprogramming is frequently observed but poorly understood in Langerhans cell histiocytosis (LCH), a rare inflammatory myeloid neoplasm. To improve molecular classification, treatment monitoring, and prognosis, we comparatively analyzed metabolite alterations in bone marrow aspirates (BMAs) from patients with various subtypes of LCH and healthy individuals. METHODS: Metabolite alterations in BMAs were identified using untargeted metabolomic profiling and quantified using targeted metabolomics. ROC curve and Kyoto Encyclopedia of Genes and Genomes analyses were used to identify potential metabolic biomarkers for diagnosis, prognosis, and therapeutic monitoring in pediatric LCH. RESULTS: The major metabolites altered in LCH included lipid/lipid-like molecules and organic acids and their derivatives, primarily involved in pathways related to choline metabolism, glycerophospholipid metabolism, and unsaturated fatty acid biosynthesis. Nine metabolites were identified as potential diagnostic biomarkers. 1-Heptadecanoyl-sn-glycero-3-phosphocholine (PC[17:0/0:0]) levels varied significantly among LCH clinical subtypes. L-kynurenine and betaine aldehyde levels helped in effectively distinguishing inflammatory from cancer-like LCH, and increased L-kynurenine and 2-arachidonoyl-1-stearoyl-snglycero-3-phosphoethanolamine levels and reduced PC(17:0/0:0) levels predicted poor prognosis. Several metabolites, including dodecanoic acid and inosine, may serve as indicators for treatment efficacy assessment in LCH with multisystem and risk organ involvement. L-kynurenine and betaine aldehyde levels were verified using targeted quantitative metabolomics, and their clinical significance was assessed. CONCLUSIONS: Alterations in BMA metabolic profiles within the LCH population and in specific metabolites may provide valuable insights into LCH pathogenesis and serve as biomarkers for diagnosis, prognosis, and therapeutic response assessment.