Gli1 Promotes The Pro-Fibrotic Function Of Monocyte-Derived Fibrocytes In Myelofibrosis

Primary myelofibrosis (MF), post-polycythemia vera (PV) MF, and post-essential thrombocytosis MF are myeloproliferative neoplasms (MPNs) characterized by progressive bone marrow (BM) fibrosis. A recent study suggested that glioma-associated oncogene-1 (GLI1), a downstream effector of the embryonic Hedgehog pathway, is implicated in the pathogenesis of BM fibrosis in MF. Because we and other investigators have found that monocyte-derived fibrocytes, rather than mesenchymal stromal cells (MSCs), induce BM fibrosis in MF, we sought to determine the role of GLI1 in MF fibrocytes. To do this, we analyzed BM biopsy sections of patients with MF using multiplex fluorescence immunohistochemistry and detected high levels of GLI1 in CD45+/CD68+/procollagen I+ fibrocytes and low levels of GLI1 in CD90+/CD105+ MSCs (P=0.009 and P=0.002, respectively). Using immunostaining, RNA in situ hybridization, gene expression, and western immunoblotting analyses of cultured BM fibrocytes or MSCs, we observed significantly higher levels of GLI1 and GLI1-induced matrix metalloproteases (MMP) 2 and 9 in MF fibrocytes than in MF MSCs or normal BM-derived fibrocytes (P