FIGURE 4.

An outline of the P-selectin/TGF-β circuit leading to disease progression in the Gata1^low mouse model of myelofibrosis. We propose that in Gata1^low mice, hematopoiesis in the spleen is sustained by a circuit between P-selectin and TGF-β and contributes to disease progression. This circuit is triggered by the abnormal expression of P-selectin on megakaryocytes (MK) that leads to neutrophilmegakaryocyte emperipolesis, increasing TGF-β content in the surrounding microenvironment and resulting in fibrocyte activation. Activated fibrocytes establish, possibly through P-selectin, peripolesis with MK forming “myelofibrosis-related stem cell niches” that sustain proliferation of the malignant stem cells in spleen generating more megakaryocytes and more neutrophils, establishing an amplification loop that contributes to disease progression. This loop may also determine hematopoietic failure and fibrosis in bone marrow. Neu, neutrophil; nu, nucleus; Pr, fibrocyte protrusion; yellow arrow, immature hematopoietic cell; yellow arrowheads, TGF-β-immuno, gold particles. The scale allows appreciation of the splenomegaly experienced by Gata1^low mice