PNC M6C2 "Investimento 2.1: Rafforzamento e potenziamento della ricerca biomedica del SSN" Leukemic Cell And Microenvironment Interactions as the Culprit of Chronicity in CLL

Chronic lymphocytic leukemia (CLL) is a paradigmatic example of a chronic neoplasia affecting the elderly population with a high socio-economic burden for patients, care-givers and the Italian National Health System. CLL is the most common leukemia among the adults in the Western countries and its incidence is rising due to the increasing life expectancy of the general population. In addition, CLL is characterized by a high prevalence due to a long median overall survival, in the order of decades, due to the long natural history of the disease but also to the therapeutic advancements with the use of novel chemo-free targeted therapies. Despite this progress, the disease remains virtually incurable, and therapy merely controls CLL symptoms. The global burden of disease remains high, with premature mortality and several years of healthy life lost due to patient¿s disability, reflected in an age-adjusted DALY (Disability Adjusted Life Years) rate of 17.13/100.00 persons, with a 34% increase of DALYs between 1990 and 2019 in Western Europe. Interestingly, CLL is clinically very heterogeneous with some patients experiencing an indolent disease course with no or delayed need of therapy while others develop a progressive malignancy needing more aggressive treatment. Rarely, it evolves into a lethal high-grade lymphoma (Richter transformation - RT). Clinical heterogeneity reflects an underlying biological heterogeneity characterized by a complex intertwining between genetic defects and microenvironmental stimuli, the latter including those occurring through stimulation of surface receptors such as the B Cell Receptor (BcR) or Toll-like Receptors (TLRs) as well as originating from non-neoplastic cells in the microenvironment, including T lymphocytes and macrophages. In this project, we aim at investigating the crucial pathways and molecules that are responsible for the chronic behavior of the disease and for its clinical progression occurring in a portion of patients. In particular we are proposing 3 distinct but interconnected aims that include: 1) the analysis of the biological factors influencing chronicity and progression of CLL, including the interplay between microenvironmental factors like BcR and TLRs stimulation and specific gene aberrations such as NOTCH1; 2) the analysis of signaling pathway activation and epigenetic modifications occurring in proliferating CLL cells activated in infiltrated lymphoid tissues in comparison with the majority of resting circulating leukemic B cells; 3) the analysis of the contribution of non-neoplastic cells in the CLL microenvironment, including T cells and macrophages, through spatial resolution of transcriptomic profiles. The results obtained in our project will allow the identification of potential markers of chronicity and/or progression that, consequently, may also become prognostic tools as well as novel targets for therapeutic purposes. This knowledge might be exploited toward a more personalized management of our patients, avoiding unnecessary psychologic and economic burden in those patients who do not need continuous follow-up, while focusing the medical resources on those who are bound to experience a life-threatening progression. A more effective management will also help individual patients and care-givers to reduce logistic, economic and psychologic stress and will ultimately optimize costs and reduce the economic burden for the NHS in general.