Parallel single-cell metabolic analysis and extracellular vesicle profiling reveal vulnerabilities with prognostic significance in acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive disease with a high relapse rate. In this study, we map the metabolic profile of CD34 + (CD38 low/- ) AML cells and the extracellular vesicle signatures in circulation from AML patients at diagnosis. CD34 + AML cells display high antioxidant glutathione levels and enhanced mitochondrial functionality, both associated with poor clinical outcomes. Although CD34 + AML cells are highly dependent on glucose oxidation and glycolysis for energy, those from intermediate- and adverse-risk patients reveal increased mitochondrial dependence. Extracellular vesicles from AML are mainly enriched in stem cell markers and express antioxidant GPX3, with their profiles showing potential prognostic value. Extracellular vesicles enhance mitochondrial functionality and dependence on CD34 + AML cells via the glutathione/GPX4 axis. Notably, extracellular vesicles from adverse-risk patients enhance leukemia cell engraftment in vivo. Here, we show a potential noninvasive approach based on liquid ‘cell-extracellular vesicle’ biopsy toward a redefined metabolic stratification in AML. The role of metabolism in acute myeloid leukaemia (AML) onset remains to be explored. Here, the authors explore the metabolic landscape of AML cells and the signature of extracellular vesicles (EVs) in peripheral blood and show that circulating EVs regulate leukaemia (stem) cell metabolic reprogramming.