PF652 DEVELOPMENT OF DILATED CARDIOMYOPATHY AND CONGESTIVE HEART FAILURE IN A MURINE MODEL OF JAK2V617F‐POSITIVE MYELOPROLIFERATIVE NEOPLASM

Background: The myeloproliferative neoplasms (MPNs) are clonal hematological malignancies characterized by hematopoietic stem cell expansion and overproduction of mature blood cells. Patients with MPNs suffer from many debilitating complications such as arterial or venous thrombosis, with cardiovascular events being the leading cause of morbidity and mortality in these patients. The acquired kinase mutation JAK2V617F plays a central role in these disorders. Endothelial cells (ECs) carrying the JAK2V617F mutation can be detected in patients with MPNs. Aims: In this work, we tested the hypothesis that altered vascular endothelium function contributes to the increased cardiovascular risk in patients withJAK2V617F‐positive MPNs. Methods: JAK2V617F Flip‐Flop (FF1) mice and Tie2‐Cre mice were crossed to generate the Tie2FF1 mice, in which the human JAK2V617F is expressed specifically in hematopoietic cells and vascular ECs, so as to model the human diseases in which both the hematopoietic stem cells and ECs harbor the mutation. All mice were fed a standard chow diet. Results: The Tie2FF1 mice develop an MPN‐like phenotype with neutrophilia, thrombocytosis, significant splenomegaly, and greatly increased hematopoietic stem cells as previously reported. Previously, we demonstrated that the JAK2V617F‐bearing ECs display altered hematopoietic cytokine expressioncompared to JAK2WT ECs and promote the expansion of JAK2V617F‐mutant stem cells in preference to JAK2WT cells in vivo . We also found that the JAK2V617F‐bearing ECs display increased cell proliferation, cell migration, and angiogenesis in vitro . Here, to study the effects of the JAK2V617F mutation on endothelial thrombogenic potential, we isolated primary murine lung ECs from Tie2FF1 and control mice and exposed the cells to pulsatile unidirectional flow at 66 dyne/cm 2 shear stress. Flow cytometry analysis revealed up‐regulation of cell adhesion molecules CD31 and E‐selectin on both unsheared and sheared JAK2V617F‐mutant ECs compared to WT controls. In addition, we observed an increased incidence of sudden death during performance of procedures (e.g. submandibular bleeding) in the Tie2FF1 mice compared to age‐matched littermate controls (7.7% vs. 0% before 20 wk of age; 42.9% vs. 0% after 20 wk of age). Transthoracic echocardiography revealed decreased ejection fraction (47% vs. 69%, P  = 0.004) and fractional shortening (23% vs. 38%, P  = 0.006), as well as increased left ventricular end‐diastolic volume (78 μl vs. 56 μl, P  = 0.003) in 20–22 wk old Tie2FF1 mice compared to age‐matched Tie2‐cre littermate controls. These abnormalities were not detected at 10–12 wk of age. Pathological evaluation revealed increased heart mass and presence of pulmonary edema in the Tie2/FF1 mice. Summary/Conclusion: Our studies suggest that there is an age‐related dilated cardiomyopathy and congestive heart failure in our MPN murine model in which both the blood cells and vascular ECs express the JAK2V617F mutation. Further work is ongoing to examine the causes of the cardiovascular dysfunction and the roles of JAK2V617F‐mutant blood cells and/or vascular ECs in the development of dilated cardiomyopathy and heart failure in the Tie2FF1 mice.