JAK2V ₆₁₇ F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms

Abstract

Significance The myeloproliferative neoplasms (MPNs) are a group of hematological malignancies characterized by increased numbers of myeloid blood cells, such as platelets, erythrocytes, and neutrophils. The main causes of illness and death in patients with MPNs are arterial and venous clotting and also, conversely, bleeding complications. However, the causes of these conditions are poorly understood. In this paper, we use a mouse model of MPNs to determine the cell types responsible for abnormal clotting in MPNs. We demonstrate that endothelial cells, the cell type that lines all blood vessels, have a significant role to play in MPN bleeding complications, potentially identifying a new cellular target for MPN therapies.

Dynamin 2–dependent endocytosis is required for normal megakaryocyte development in mice

“…[50][51][52] Recent studies confirmed the specificity of the Pf4-Cre model to mature MKs and platelets using Mpl and JAK2 deletion or JAK2-V617F expression. 24,[53][54][55] Accordingly, Dnm2 fl/fl Pf4-Cre mice had normal erythrocyte counts and volumes, and granulocyte and monocyte counts were increased only by 30%, whereas these parameters are severely altered in JAK2-V617F knockin mouse models. [56][57][58][59][60] DNM2 deletion in HSPCs is expected to severely alter erythropoiesis, because ubiquitous Dnm2 deletion is lethal in mice before embryonic day 8.5, 8 a stage in which first erythrocytes circulate and the heterozygous DNM2 loss-of-function mutation V235G induced by chemical mutagenesis is associated with iron deficiency anemia due to impaired transferrin uptake in mice.…”

“…Interestingly, specific JAK2-V617F expression in MKs using the Pf4-Cre model does not recapitulate the MF of Dnm2 fl/fl Pf4-Cre mice or that of JAK2-V617F knockin mice. 53 It is likely that JAK2-V617F expression is low in Jak2 V617F Pf4-Cre MKs and platelets compared with that of endogenous JAK2, making it poorly effective in inducing Mpl downmodulation. Given that we observed an increase in both multipotential hematopoietic progenitor and MK-specific CFUs in vitro, it is likely in each group; ***P , .0001).…”

The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm

“…28 Figure 1). Additionally, JAK2V 617 F expression resulted in increased Mpl expression (supplemental Figure 1).…”

Advances and challenges in the management of essential thrombocythemia

“…Furthermore, recent studies have shown high levels of membrane bound as well as plasma soluble P-, E-and L-selectins, indicating that activated platelets and endothelial cells may promote thrombus formation [Karakantza et al 2004]. JAK2V617F+ endothelial cells have been found to contribute to clot formation in mice [Etheridge et al 2014]. A high level of activated protein C resistance was recently found in ET patients with previous thrombosis [Brinkman et al 2005].…”