Atherothrombosis in JAK2V617F clonal hematopoiesis

Project Summary/Abstract Clonal hematopoiesis (CH) occurs when somatic mutations provide a fitness advantage to hematopoietic stem and progenitor cells, leading to clonal expansion of mutant blood cells. CH is highly prevalent in the elderly and has emerged as a major independent risk factor for atherosclerotic cardiovascular disease (CVD). Among the common genetic variants of CH, individuals with JAK2V617F CH have an outstanding risk of myocardial infarction and of venous and arterial thrombosis. JAK2V617F variants are present in 3-4% of a general European population and are associated with increased thrombotic risk at very low allele burden. There is no approved therapy for this risk. We have demonstrated increased atherosclerosis in chimeric mice that model JAK2V617F CH, involving elevated inflammasome activation and IL-1β production. While atherosclerosis in CH has been intensively studied, the impact and mechanisms of CH driven atherothrombosis have not been extensively investigated. Our preliminary studies have shown accelerated atherothrombosis in Jak2VF CH models. While our studies suggest the underlying importance of JAK2V617F platelets, myeloid cells and erythrocytes as well as the cross-talk from mutant to wild type cells in atherosclerosis and atherothrombosis, the relative importance of different blood cell types and of cross-talk between cell types need to be more rigorously assessed. We propose to use novel mouse models to interrogate the role of different blood cells and the relevant pathways and mechanisms involved in accelerated atherosclerosis and atherothrombosis in JAK2V617F CH. Elucidation of the different proposed mechanisms may lead to the development of precision therapeutic approaches to reduce atherosclerotic and atherothrombotic risk in JAK2VF CH.