Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) that leads to progressive bone marrow (BM) fibrosis. Although the cellular mutations involved in the PMF pathogenesis have been extensively investigated, the sequential events that drive stromal activation and fibrosis by hematopoietic-stromal cross-talk remain elusive. Using an unbiased approach and validation in MPN patients, we identified that the differential spatial expression of the chemokine CXCL4/platelet-factor-4 (PF4) marks the progression of fibrosis. We demonstrate that the absence of hematopoietic CXCL4 ameliorates the MPN phenotype, reduces stromal cell activation and BM fibrosis and decreases 1) the activation of pro-fibrotic pathways in megakaryocytes, 2) inflammation in fibrosis-driving cells and 3) JAK/STAT activation in both megakaryocytes and stromal cells in three murine PMF models. Our data indicate that higher CXCL4 expression in MPN has pro-fibrotic effects and is a mediator of the characteristic inflammation. Therefore, targeting CXCL4 might be a promising strategy to reduce inflammation in PMF.