Abstract
Fibrotic remodeling of the bone marrow (BM) niche is a characteristic feature of myelofibrosis (MF) that contributes to disease progression. In MF, mesenchymal stromal cells (MSCs) produce excessive amounts of inflammatory cytokines and extracellular matrix, leading to BM fibrosis, impaired blood production, extramedullary hematopoiesis, and progressive BM failure. While the genetic events that initiate MF in hematopoietic cells are well defined, our understanding of the mechanisms responsible for BM fibrosis remains incomplete. Here, we show that transcription factor EBF1 is a key regulator of the fibrotic gene program in mouse and human MSCs. EBF1 is upregulated in pre-fibrotic MSCs, while mice with MSC-specific deletion of Ebf1 exhibit reduced BM fibrosis, decreased expansion of myeloid cells and splenomegaly when transplanted with hematopoietic progenitors harboring the MF driver mutation MPL (W515L) . Moreover, we identify ITGB8 as an EBF1-regulated gene with therapeutic potential. MF mice treated with ITGB8-neutralizing antibodies or with MSC-specific Itgb8 deletion show reduced disease burden, as indicated by decreased marrow fibrosis, significantly reduced frequencies of MPL mutant cells, and reduced inflammation in the BM. Our data indicate that targeting the EBF1-ITGB8 axis in the MF MSCs may have therapeutic benefits.