MKs play a central role in MPN pathogenesis. The MPL/JAK2 pathway is activated by the 3 MPN-restricted mutations (JAK2V617F, CALR mutants, and MPL mutants) placing MK hyperplasia and eventually dysplasia as a central determinant in MPN. MKs are mainly involved in platelet production, and also play an important role in the hematopoietic niche by regulating HSCs, remodeling the marrow by secretion of TGF-β1 and other cytokines (platelet-derived growth factor [PDGF], vascular endothelial growth factor [VEGF]) which ultimately lead to MF, and also inducing a neo-osteogenesis by inducing an osteoblastic differentiation through TGF-β1 and inhibiting osteoclast differentiation through osteoprotegerin. Furthermore, MKs secrete numerous inflammatory cytokines such as IL1α. The mechanisms of local activation of TGF-β1 are poorly known. OPG, osteoprotegerin; RANK, receptor activator of NF-κB; RANKL, RANK ligand; TGF, transforming growth factor; TSP, thrombospondin. Professional illustration by Somersault18:24.