Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension through ALK1

Pulmonary hypertension (PH) is known to be associated with hematological disorders including myeloproliferative neoplasms (MPNs). JAK2V617F is the most frequent driver mutation among the MPNs, and age-related clonal hematopoiesis with JAK2V617F have been recently identified in the individuals without hematological disorders. However, mechanistic relevance between hematopoietic JAK2V617F and PH is largely unclear. Here, we revealed that hematopoietic JAK2V617F markedly promoted PH with pulmonary arterial remodeling in response to chronic hypoxia in both JAK2V617F-Tg (JAK2V617F) mice and WT recipient mice transplanted with JAK2V617F bone marrow cells. JAK2V617F Ly6G+ neutrophils were substantially accumulated in pulmonary arterial regions, accompanied by increases in elastase activities and neutrophil-related chemokines after exposure to chronic hypoxia in these JAK2V617F mice and recipient mice. Expression of Acvrl1 which encodes ALK1 was gradually increased in JAK2V617F hematopoietic cells in accordance with the differentiation from bone marrow stem/progenitor cells to mature neutrophils in the lung. ALK1-Smad1/5/8 was upregulated by JAK2V617F-mediated STAT3 activation, whereas ALK1 inhibition completely rescued the development of PH and pulmonary arterial remodeling in JAK2V617F mice. Finally, we found significantly high prevalence of JAK2V617F in PH patients without hematological disorders. These findings together indicate that clonal hematopoiesis with JAK2V617F causally leads to PH development through ALK1.