Fibrocytes drive JAK2V617F-mutated myelofibrosis: pitavastatin reverses marrow fibrosis and anemia.

Bone marrow (BM) fibrosis in primary and post-polycythemia vera/essential thrombocythemia myelofibrosis (MF) has traditionally been considered a reactive process driven by cytokines, such as transforming growth factor β1 (TGF-β1), primarily produced by neoplastic megakaryocytes and platelets. These cytokines promote the differentiation of wild-type mesenchymal stromal cells into collagen- and fibronectin-producing myofibroblasts, thereby inducing BM fibrosis. However, hematopoietic-derived collagen-producing cells of monocyte lineage, termed fibrocytes, have also been implicated in this process. Here, we demonstrate that fibrocytes constitute a major collagen-producing cell population in the BM of patients with JAK2V617F-mutated MF, with additional contributions from myofibroblasts. Analysis of BM samples from patients with JAK2V617F-mutated myeloproliferative neoplasms (MPNs) revealed that fibrocytes accounted for nearly two-thirds of collagen-producing cells, whereas myofibroblasts represented a smaller subset. Using BM-derived fibrocytes from Jak2V617F transgenic mice (Jak2V617F mice), we performed a high-throughput drug screen and identified statins as inhibitors of fibrocyte proliferation in vitro. In vivo, pitavastatin treatment reduced fibrocyte numbers, ameliorated BM fibrosis, and improved anemia in Jak2V617F mice. Pitavastatin also decreased TGF-β1 production by neoplastic fibrocytes, resulting in reduced myofibroblast expansion. Peripheral blood-derived fibrocytes from patients with JAK2V617F-mutated MPNs were similarly sensitive to pitavastatin in vitro. Together, these findings suggest that fibrocytes substantially contribute to BM fibrosis in JAK2V617F-mutated MF and support further investigation of pitavastatin as a potential antifibrotic strategy in this molecular subset.