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The leading hypothesis underlying the project of the Unit of Clinical Epidemiology of the IRCCS Policlinico S. Matteo of Pavia is that dissection of deranged function of the megakaryocytic and endothelial cell lineages in myelorpolfierative neoplasms, in particular in Myelofibrosis, can help designing novel therapeutic approaches.
In the part of the project dedicated to megakaryocytes, we will evaluate whether targeting specific cells and molecules forming up bone marrow (BM) niches regulating megakaryocytopoiesis would result in correcting abnormal proliferation and differentiation of these cells that typically occur in MPN, particularly PMF. Nowdays, several therapeutic agents (i.e. bevacizumab, anti-h TGF-β mAbs, immunomodulatory agents) inhibiting either the production and/or the activity of fibrogenic and angiogenic cytokines are available. In in-vitro cellular systems we will first study the impact of a number of key environmental variables on the megakaryocytic differentiation of PMF hematopoietic stem cells, including matrix proteins and co-cultures with mesenchymal stem cell-derived osteoblast or endothelial cells. Specific areas of focus for mechanistic insight will include pathways underlying several integrins (alpha2beta1, alpha4beta1, alpha5beta1) and receptors (GPIIbIIIa, TGF-βR) expressed on megakaryocytes, including the role of CXCR4/SDF1 axis. Then, we will evaluate in these cellular systems the effects of some of the drugs indicated above.
In the part of the project dedicated to endothelial progenitors, we will focus on endothelial cells, since recent findings indicated that high degree of endothelial progenitor cell (EPC) mobilization into peripheral blood (PB) is a distinctive feature of PMF. This behaviour is reminiscent of the constitutive release of CD34+ cells in PB and their accumulation in extramedullary sites, that are credited a central role in the progression of the disease. The existence of a BM reservoir of EPC and their involvement in neovascularization in proliferative diseases has attracted considerable interest because EPC constitute a novel target for therapeutic interventions. Little is known, however, on the phenotype of EPC in PMF and whether their ablation may be beneficial in limiting the progression of the disease; it is also still debated whether subpopulations of EPC harbor disease-associated mutations. The hypothesis we want to address is that EPC mobilization, seeding and proliferation in extramedullary organs underlies the switch from a dormant, non angiogenic to an active, angiogenic and heterotopic myeloproliferation, and that EPC represent valuable targets of therapy. First, the phenotype of circulating EPC from PMF patients at different stages of disease progression will be characterized by comparative analysis of gene expression (Affymetrix platform). We expect to identify some specific features of PMF-derived EPC that could be correlated with disease progression, and possibly to discover surface markers useful for characterization and targeting. We will also address whether a perturbation of the SDF1-CXCR4 axis and/or an increased protease activity in the BM microenvironment regulate EPC mobilization in PMF, as we have shown to occur for CD34+ cells. We will investigate the in-vitro growth and maturation of circulating EPCs and vascular wall mature ECs in PMF patients and the correlation with genotype and disease stage. The involvement of SDF1-CXCR4 axis and increased metalloprotease activity on EPC circulation, and the effects of drugs targeting these molecules, will be assessed in animal models.
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