Endothelial dysfunction in clonal hematopoiesis and its contribution to cardiovascular complications

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Military personnel are at an increased risk of developing hematopoietic mutations due to their exposure to various environmental hazards. Recently, it has been reported that as low as 2% mutant blood cells can produce a 2-4 fold increase in cardiovascular diseases (CVDs) in individuals with clonal hematopoiesis of indeterminate potential (CHIP), even in the absence of other risk factors. The acquired kinase mutation JAK2V617F is one of the common mutations associated with CHIP. Individuals with JAK2V617F mutant CHIP have 12 times the risk of CVDs compared to individuals without any CHIP-associated mutation. JAK2V617F also plays a central role in most patients with myeloproliferative neoplasms (MPNs), which are clonal stem cell disorders characterized by hematopoietic stem cell expansion and overproduction of mature, often dysfunctional blood cells. Patients with MPNs suffer from many debilitating complications including both venous and arterial thrombosis, with cardiovascular events being the leading cause of morbidity and mortality in these patients. Despite the substantial progress in our understanding of hemostasis and thrombosis, remarkably little is known about the mechanisms that contribute to the increased thrombosis risk in patients with MPNs. Vascular endothelial cells (ECs) carrying the JAK2V617F mutation can be detected in many patients with MPNs. Our recent work with a JAK2V617F-positive murine model of MPN, in which the mutation is expressed in both blood cells and vascular ECs, showed that the mice developed spontaneous heart failure with a thrombosis and vasculopathy phenotype. This model contrasts other murine models of CHIP-associated hematopoietic mutations, in which mice develop CVDs only when challenged with risk factors such as high-fat diet. This difference suggests that mutant ECs can accelerate cardiovascular dysfunction. Based on these studies, we hypothesize that the JAK2V617F mutation induces endothelial dysfunction to accelerate CVDs in patients with MPNs and in people with CHIP. In particular, we propose the following three specific aims: Aim 1) To test the hypothesis that the JAK2V617F mutation increases endothelial thrombogenic potential by upregulating a major EC adhesion molecule E-selectin, which in turn leads to increased adhesion of JAK2V617F mutant leukocytes. Aim 2) To test the hypothesis that JAK2V617F induces premature endothelial senescence, which is a major risk factor for CVDs and vascular thrombosis. Aim 3) To study how JAK2V617F mutant ECs promote the development of CVD in a murine model of JAK2V617F-positive CHIP. The roles of thrombopoietin and its receptor MPL in JAK2V617F-induced cardiovascular dysfunction will be explored. A better understanding of how hematopoietic mutations contribute to cardiovascular diseases will improve our treatment of two of the most important human health threats, cancer and heart disease.