Caratterizzazione del profilo metabolico e delle dipendenze da substrato delle cellule di sindrome di Richter

Richter’s syndrome (RS) is a high-grade aggressive lymphoma, with a clinical poor outcome, developed in patients diagnosed with chronic lymphocytic leukemia (CLL). Different features underlining disease pathogenesis are still largely undefined, including metabolism, which is a hallmark of cancer cells. The aim of this work was to define the metabolic profile and substrate dependencies of RS cells, exploiting 4 patient-derived xenograft (PDX) models available in the lab. By comparing transcriptomic data from RS-PDXs and primary CLL samples, a different expression profile was highlighted with oxidative phosphorylation, reactive oxygen species pathway, and fatty acids metabolism being the most significantly enriched gene sets in RS. These data were supported by the measurement of the activity of key enzymes controlling the main metabolic pathways, with RS cells characterized by an elevated metabolic rate sustained by an increased glucose and glutamine uptake compared to CLL. Moreover, RS cells showed the activation of anabolic processes that resulted in the synthesis of nucleotides and fatty acids, necessary to sustain high proliferation rate. In line with these results, treatment of RS cells with selective metabolic inhibitors pointed out their dependencies from glucose and glutamine, at variance with CLL cells that mainly rely on fatty acids. Overall, these data suggest a metabolic rewiring of RS cells as a consequence of disease evolution from CLL, opening for translational opportunities.