Faculty Collaboration Database

Bleeding diathesis in mice lacking JAK2 in platelets. Blood Adv 2021 Aug 10;5(15):2969-2981

Date

08/04/2021

Pubmed ID

34342643

Pubmed Central ID

PMC8361459

DOI

10.1182/bloodadvances.2020003032

Abstract

The tyrosine kinase JAK2 is a critical component of intracellular JAK/STAT cytokine signaling cascades that is prevalent in hematopoietic cells, such as hematopoietic stem cells and megakaryocytes (MKs). Individuals expressing the somatic JAK2 V617F mutation commonly develop myeloproliferative neoplasms (MPNs) associated with venous and arterial thrombosis, a leading cause of mortality. The role of JAK2 in hemostasis remains unclear. We investigated the role of JAK2 in platelet hemostatic function using Jak2fl/fl Pf4-Cre (Jak2Plt-/-) mice lacking JAK2 in platelets and MKs. Jak2Plt-/- mice developed MK hyperplasia and splenomegaly associated with severe thrombocytosis and bleeding. This notion was supported by failure to occlude in a ferric chloride carotid artery injury model and by a cremaster muscle laser-induced injury assay, in which Jak2Plt-/- platelets failed to form stable thrombi. Jak2Plt-/- platelets formed thrombi poorly after adhesion to type 1 collagen under arterial shear rates. Jak2Plt-/- platelets spread poorly on collagen under static conditions or on fibrinogen in response to the collagen receptor GPVI-specific agonist, collagen-related peptide (CRP). After activation with collagen, CRP, or the CLEC-2 agonist rhodocytin, Jak2Plt-/- platelets displayed decreased α-granule secretion and integrin αIIbβ3 activation or aggregation, but showed normal responses to thrombin. Jak2Plt-/- platelets had impaired intracellular signaling when activated via GPVI, as assessed by tyrosine phosphorylation. Together, the results show that JAK2 deletion impairs platelet immunoreceptor tyrosine-based activation motif signaling and hemostatic function in mice and suggest that aberrant JAK2 signaling in patients with MPNs affects GPVI signaling, leading to hemostatic platelet function.

Author List

Eaton N, Subramaniam S, Schulte ML, Drew C, Jakab D, Haberichter SL, Weiler H, Falet H

Authors

Herve Falet PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Platelets
Disease Susceptibility
Hemorrhage
Hemostasis
Janus Kinase 2
Mice
Mice, Knockout
Platelet Activation
Platelet Membrane Glycoproteins
Thrombocytosis