Potential pathogenetic mechanisms in myelofibrosis with myeloid metaplasia (MMM).

In mice, either thrombopoietin (TPO) overexposure or intrinsic GATA-1 underexpression results in megakaryocyte proliferation and the MMM phenotype. Megakaryocytes in such mice as well as in human MMM under-express the TPO receptor (c-mpl). This in turn might lead to decreased TPO clearance and local TPO excess. That might further contribute to megakaryocyte accumulation and stromal cell stimulation of cytokine production. Abnormal release of transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), and neutrophil elastase (NE) might result from pathologic interaction between MMM megakaryocytes and neutrophils. These cytokines, either directly or indirectly through vascular endothelial growth factor (VEGF) and osteoprotegerin (OPG), might contribute to several components of the stromal reaction in MMM.