ABNORMALITIES OF THE ENDOTHELIAL LINEAGE IN PRIMARY MYELOFIBROSIS

Primary Myelofibrosis (PMF) belongs to the family of Myeloproliferative neoplasms (MPNs), a heterogeneous group of related clonal malignant diseases characterized by the oncogenic transformation of the multipotent hematopoietic progenitor cell (HPC), which leads PMF patients to develop massive bone marrow (BM) fibrosis. Clinical hallmarks also include progressive splenomegaly, anemia and weakness due to ineffective hematopoiesis and excessive production of pro-inflammatory cytokines, which play a central role in mediating increased deposition of BM stromal fibers. So far, no curative treatment for this pathology exists with the exception of allogenic stem cell transplant, thus highlighting the great need to find an alternative and less risky therapy. Although fibroblasts are directly implicated in fibrosis development, endothelial cells (ECs) can also play a role in PMF; indeed, when activated by inflammatory cytokines such as TGF-β, they undergo a process called Endothelial-to-mesenchymal transition (EndMT), leading ECs to acquire fibroblastic features. Our results show that ECs can undergo EndMT during the development of PMF both in patients and in a MPN mouse model of the disease. This process occurs during early stages of fibrotic degeneration and is primarily mediated by the release of TGF-β by megakaryocytes (MKs) and platelets. Moreover, patients with different genetic mutations inducing PMF all undergo EndMT, thus proposing it as a common mechanism of fibrosis development. We also demonstrate that TGF-β induces endogenous BMP4 and BMP6 up-regulation in splenic ECs, further sustaining EndMT phenotype. Moreover, our results show that the in vitro treatment of splenic ECs with TGF-β and BMP inhibitors can revert EndMT phenotype, thus opening the possibility to the use of specific and more targeted therapy for PMF patients to achieve fibrosis remission.