Contribution of endothelial JAKV617F expression to thrombosis
Description: The JAK2V617F mutation occurs in up to 95% of patients with myeloproliferative neoplasm (MPN)1 and in ~3% of patients with clonal hematopoiesis of indeterminate potential (CHIP).2 Among patients with MPN or CHIP, a JAK2V617F mutation increases the risk of thrombosis by up to 6-fold. Identification of how JAK2V617F+ contributes to the pro-thrombotic milieu is needed to inform the design of targeted antithrombotic strategies for JAK2V617F+ CHIP and MPNs. Current understanding of JAK2V617F+ MPN thrombotic risk assumes that thrombosis is secondary to an overabundance of clonal hematopoietic cells. However, cytoreduction in JAK2V617F+ MPNs does not completely reduce thrombosis. Additionally, endothelial cells in JAK2V617F+ MPN patients are activated.7-9 These findings suggest the vascular endothelium contributes to thrombotic risk. The overall objective of this proposal is to identify the inflammatory and thrombotic mechanisms regulated by JAK-STAT signaling in the endothelium. My central hypothesis is that aberrant JAK-STAT activity evokes an inflammatory and thrombotic cascade within the vascular endothelium leading to increased thrombosis in JAK2V617F+ CHIP and MPN. In preliminary studies, I demonstrate that both ruxolitinib and fedratinib, JAK-STAT inhibitors approved for use in JAK2V617F+ MPNs, decreased TNF-a mediated secretion of pro-adhesive VCAM, pro-inflammatory IL-6 and pro-coagulant tissue factor. Using endothelialized microfluidics, I further demonstrate that endothelial activation with TNF-a is needed to increased rolling of JAK2V617F+ MPN whole blood. Collectively, my preliminary data supports my central hypothesis that JAK-STAT activity in the vascular endothelium is responsible for thrombosis in JAK2V617F+ CHIP and MPN. To test our hypothesis, I will complete the following Specific Aims: (1) Determine whether JAK-STAT inhibition reduces adhesive interactions between endothelial cells and blood cellular components and (2) Establish whether autocrine- or paracrine-mediated interactions between JAK2V617F+-endothelial cells and JAK2V617F+-MPN blood cellular components induces inflammation and thrombosis. To accomplish these aims, I propose training objectives that are designed to enable me to develop robust endothelialized microfluidic models and to systematically evaluate immunologic pathways pertinent to JAK2V617F-driven pathophysiology.
Funder: American Heart Association
Amount: $231,000
Funding type: fellowship
Funder scheme: Career Development Award
Start date: 2021-07-01
End date: 2024-06-30
Investigators: Joan Beckman, Joan Beckman
Institution: Regents of the University of Minnesota - Twin Cities
Funded outputs count: 2
Funder award ID: 857424
OpenAlex ID: G5905249376