Putative mechanisms responsible for PMF pathogenesis. Whereas the initial molecular defect at the origin of the pathological clone is still unknown, alteration of tyrosine kinase–related signalization likely participates in the amplification of the hematopoietic clone as attested by the presence of mutations in the JAK2 and MPL genes in a proportion of PMF patients. Altered interactions between clonal CD34⁺ cells and stromal cells in the hematopoietic environment would result in an increased cytokine production by the clonal hematopoietic cells and especially by dystrophic megakaryocytes and monocytes. Increased production of hematopoietic, fibrogenic, and angiogenic growth factors would maintain hematopoietic cell proliferation (myeloproliferation) and stimulate myelofibrosis, osteosclerosis, and neoangiogenesis through activation of stromal and endothelial cells. Egress of CD34⁺ cells from the bone marrow (stem cell mobilization) would result from several mechanisms including chemokines/receptor alterations and protease release from activated neutrophils. HSC indicates hematopoietic stem cell; Mk, megakaryocyte; Mo, monocyte; Ne, neutrophil; Fb, fibroblast; Ob, osteoblast; and Oc, osteoclast.