A pathobiologic pathway linking TPO, GATA-1, and TGF-β1 in the development of myelofibrosis in mice and, possibly, of IM in humans. Both TPO^high and GATA-1^low mutations decrease the GATA-1 content of Mks (Figure 7) and induce similar Mk abnormalities, including abnormal P-selectin localization on the DMS, increased emperipolesis of neutrophils, and high levels of para-apoptosis (Figure 4).^22,32  In both cases, the animals express high levels of TGF-β1 in extracellular fluids of marrow and spleen (Table 1), while neutrophil proteases are also detected in the microenvironment surrounding the Mks in association with the fibers (Figure 4). According to these data, we propose that marrow fibrosis is caused by TGF-β1 activation of the fibroblasts. On the other hand, extramedullary hematopoiesis is the consequence not only of reductions in stem/progenitor cell niches in the marrow because of fibrosis, but also of the proteases released by the neutrophils as part of the emperipolesis process that would dislodge stem/progenitor cells by cleaving from their surface the adhesion proteins necessary for attachment to the niches.³⁷  Dislodged stem/progenitor cells would, then, have no other choice than to home and colonize lower affinity niches in other tissues.