Metabolic pathways and therapeutic opportunities in the chronic lymphocytic leukemia microenvironment

This study delves into the intricate metabolic dynamics of chronic lymphocytic leukaemia (CLL) within the tumour microenvironment (TME) of lymphoid tissues. Unlike the traditional focus on quiescent CLL cells in peripheral blood, this study aims to unravel complex metabolic behaviour of CLL cells in the lymph node compartment, where CLL cells divide and become activated.
Utilizing state-of-the-art methods, such as metabolomics, transcriptomics, and fluxomics, we found that interaction of CLL cells with adjacent cells within the TME results in significant metabolic alterations. Particularly, we discovered a shift towards glutamine dependency of CLL cells upon TME-related stimulation. Such metabolic alterations impact sensitivity of these leukaemia cells to treatments, especially to specific apoptosis inducing agents, such as venetoclax, which has become the cornerstone of CLL treatment. The study demonstrates that by targeting specific metabolic pathways, such as the electron transport chain, CLL cells can be sensitized to venetoclax treatment. This finding can be exploited for the development of innovative strategies in order to overcome drug resistance.
Additionally, the thesis explores the effects of mitochondrial glutamine transporters and the broader implications of lipid metabolism alterations in CLL. It also probes into the role of key genetic factors, such as p53, in the metabolic regulation of CLL and other B cell malignancies, unveiling new insights into potential therapeutic vulnerabilities.
Conclusively, this research not only fills critical gaps in our understanding of CLL metabolism within the TME but also paves the way for novel, targeted therapeutic interventions. By linking metabolic alterations to treatment responses, it sets the stage for more effective, personalized approaches in the management of CLL.