NOTCH1 orchestrates metabolic reprogramming, proliferation, and tissue tropism in a novel cellular model of Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by the monoclonal expansion and accumulation of mature B cells in the peripheral blood, bone marrow, and secondary lymphoid organs. Despite improvements in care, CLL remains incurable and patients often relapse or become refractory to therapy. Signalling via surface immunoglobulins as well as numerous genetic alterations, among which hyperactivating NOTCH1 mutations are the most frequent, play a crucial role in CLL pathogenesis and progression, but the synergy among them and their effects on cellular pathobiology are scarcely understood. The objective of this study is to dissect the role of NOTCH1 in CLL and investigate whether its crosstalk with B cell receptor activation bears functional consequences, with a specific focus on metabolic reprogramming. To do so, we established and validated a novel cellular model of CLL expressing an unmutated patient-derived IGHV either in a wild-type or a mutated NOTCH1 genetic background. In vitro and in vivo analyses of these cellular models reveal that NOTCH1 hyperactivation drives metabolic reprogramming, enhancing glycolysis and oxidative phosphorylation, stimulates cell proliferation, and guides tissue tropism. Lastly, we confirmed that primary CLL lymphocytes recapitulate the metabolic phenotypes observed in our cellular models. We can envision how, in the emerging framework of precision medicine, CLL patients could be stratified based on their NOTCH1 mutational status and assigned to therapeutic regimens which exploit the metabolic vulnerabilities associated with NOTCH1-mutated CLL, resulting in higher rates of disease clearance.