Megakaryocytes in myelofibrosis: mechanisms of fibrotic niche remodeling and therapeutic implications.
Key claim: Dysplastic megakaryocytes drive myelofibrosis niche remodeling mainly by coordinating stromal, immune, and endothelial responses via TGF-β1, PF4/CXCL4 and related mediators, and durable fibrosis reversal will require targeting mutant progenitors plus stromal activation and matrix deposition—not JAK inhibition alone.
Abstract
Myelofibrosis is a clonal myeloproliferative neoplasm characterized by progressive remodeling of the bone marrow microenvironment. Megakaryocyte (MK) abnormalities are defining histological features of prefibrotic and overt primary myelofibrosis and contribute to disease pathogenesis. Dysplastic MKs can directly modify the pericellular extracellular matrix (ECM), but their main fibrogenic influence comes from coordinating stromal, immune, and endothelial responses. This Review synthesizes evidence linking abnormal MK biology to fibrotic progression and examines its implications for biomarkers and therapy. In normal bone marrow, MKs regulate hematopoietic stem cell quiescence, organize the ECM and vascular niches, and participate in immune regulation. Hematopoiesis driven by mutations in JAK2, CALR, or MPL, together with chronic inflammation, disrupts these functions. Dysplastic MKs release or activate transforming growth factor-β1 (TGF-β1), platelet factor 4 (PF4/CXCL4), and other profibrotic mediators and interact with neutrophils, monocytes, mesenchymal stromal cells, and endothelial cells. These interactions promote stromal activation, monocyte-to-fibrocyte differentiation, vascular and osteogenic remodeling, and ECM accumulation. As disease progresses, collagen cross-linking and altered bone marrow mechanics help stabilize the remodeled niche. Janus kinase inhibitors reduce splenomegaly and symptoms, but pharmacological therapies have not been shown to consistently reverse established bone marrow fibrosis. Durable disease modification will likely require sustained suppression of mutant progenitors and dysplastic MK production together with inhibition of stromal activation, inflammatory signaling, and matrix deposition or cross-linking. Clinical improvement, suppression of abnormal megakaryopoiesis, reduction in profibrotic signaling, and regression of bone marrow fibrosis should therefore be assessed separately using measures matched to each therapeutic mechanism.
Why this matters
Dysplastic megakaryocytes drive myelofibrosis niche remodeling mainly by coordinating stromal, immune, and endothelial responses via TGF-β1, PF4/CXCL4 and related mediators, and durable fibrosis reversal will require targeting mutant progenitors plus stromal activation and matrix deposition—not JAK inhibition alone.