Phd in IINNOVATION IN IMMUNO-MEDIATED AND HEMATOLOGICAL DISORDERS

Thesis title: Metabolic profiling in chronic lymphoproliferative diseases

The PhD research program explored the metabolic reprogramming of the B-cell lymphoproliferative disorder, the chronic lymphocytic leukemia (Study N. 1), its correlation with the prognosis and the response to BTK-inhibitors treatment (Study N. 2) and the metabolic analysis in another rare B-cell disorders, the Hairy Cell Leukemia (Study N. 3). Metabolic reprogramming is one of the fundamental characteristics of cancer cells. In particular, an exceeding activation of the cellular metabolism contributes to the uncontrolled growth and proliferation of cancer cells, which is based on a particularly high demand for energy and anabolic precursors (amino acids, fatty acids, nucleotides) which are essential for the rapid building of cellular structures (proteins, lipids, nucleic acids). Among the different cellular metabolic pathways, the increased glycolytic flux, the exploitation of alternative carbon source like glutamine and the increase in fatty acid metabolism are those usually exploited by malignant cells, thus resulting in a metabolic reprogramming and a new bioenergetic phenotype. Metabolic reprogramming is strictly related to the aberrant activation of signal transduction pathways, although the causal relationship between altered signalling and redesigned metabolism is currently under review. In fact, according to recent works, a feedback mechanism is involved in which metabolites can control signal fluxes through specific sensor kinases, which in turn monitor cell bioenergetic status. Chronic Lymphocytic Leukemia is an indolent malignancy characterized by a significant clinical variability, which reflects an intrinsic biologic heterogeneity. Recent evidence indicates that CLL cells have active metabolic processes, which can be targeted for therapeutic interventions, ultimately rewiring the metabolic status of CLL cells. In addition, alterations of pro-apoptotic pathway and of signal transduction pathways (STP) are frequent events in Chronic Lymphocytic Leukemia (CLL) or other B cells malignancies, such as Hairy Cell Leukemia (HCL), representing one of the causes of treatment resistance. Recent evidence shows that genetic alterations and the aberrant activation of STP of CLL cells have a profound influence on the metabolic activity of B cells. Therefore, cancer cell metabolism represents a potential target for therapeutic intervention in CLL cells that may be integrated with conventional chemotherapy and molecularly targeted agents. In solid tumors, in fact, a great number of studies supports this approach. The aim of my PhD program research was to expand the knowledge on leukemia cell metabolic phenotypes evaluating the two intracellular ATP-generating pathways: glycolysis and oxidative phosphorylation. This work was conducted in cell lines and primary cells of patients affected by CLL and other B-cell malignancies, in order to establish new prognostic markers and to identify novel therapeutic targets.