1) DECODING THE EXTRACELLULAR VESICLES-DRIVEN COMMUNICATION IN THE MICROENVIRONMENT OF HAIRY CELL LEUKEMIA TO IMPROVE PATIENT CARE MANAGEMENT
Primary aims
1. Verify whether Hairy cell Leukemia (HCL) patients at different status (at diagnosis, in complete remission > 2 years, or relapsed meeting treatment indications) display specific extracellular vesicles (EV)-based signatures
2. Verify whether in HCL patients at different status (at diagnosis, in complete remission > 2 years, relapsed meeting treatment indications) the EV-based signatures are different
Secondary aims
- Elucidate whether plasma -derived EVs of HCL patients, of healthy donors (HD), and of in vitro Hairy cells (HCs)-derived EVs may functionally educate the immune microenvironment
- Identify whether plasma-derived EVs of HCL patients and of HD and in vitro HCs-derived EVs play a role in tumor immune evasion
- Elucidate whether plasma-derived EVs of HCL patients and of HD may functionally affect the isolated HCs
- Understand whether plasma-derived EVs from HCL patients and from HD and in vitro HCs-derived EVs might shape the stromal microenvironment toward fibrosis
2) UNRAVELING THE ROLE OF EXTRACELLULAR VESICLES-DRIVEN SENESCENCE IN MYELOPROLIFERATIVE NEOPLASMS
To date, there is an urgent medical need for more efficient and novel therapeutic options in MPN. Here, we aim to assess whether EV-driven cell senescence play a pathogenetic role in MPN. The goal of this project is to identify possible EV-based biomarkers of senescence according to gender, which are disease-specific, MPN biology-related, and predictive of short-term outcome in terms of Event-Free Survival (thrombosis, infections, death and eventually disease progression (from PV/ET to MF and/or from PV/MF to blast phase) and to define personalized targets for new therapeutic approaches. To this end, our plan will develop along innovative lines of research including liquid biopsy and multidimensional bio-molecular analysis. Main biological QUESTIONS and AIMS: a) Is cell senescence phenotype present in peripheral blood (PB)/bone marrow (BM) EVs from MPN patients? b) Is inflammation a driver of cell senescence through EVs release? c) Are circulating EVs from MPN patients driving epigenetic information of cell senescence? d) Are circulating EVs from MPN patients able to modify surrounding cells in vitro?; e) can we identify a personalized short-term prognostic index based on the EVs-driven cell senescence signature? All the questions will include the comparisons among diseases (ET, PV, MF), genders and aged-matched healthy donors (HD). The working hypothesis is that the inflammatory/immune derangement in MPN is: i) the consequence of the selection of immune cells harboring a specific senescence signature, and/or ii) the consequence of the adaptation of immune cells to the inflammatory microenvironment, mediated by the establishment of EV-based mechanisms of senescence.
