Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils

Yusuke Kimishima, Tomofumi Misaka (), Tetsuro Yokokawa, Kento Wada, Koki Ueda, Koichi Sugimoto, Keiji Minakawa, Kazuhiko Nakazato, Takafumi Ishida, Motohiko Oshima, Shuhei Koide, Kotaro Shide, Kazuya Shimoda, Atsushi Iwama, Kazuhiko Ikeda () and Yasuchika Takeishi
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Yusuke Kimishima: Fukushima Medical University
Tomofumi Misaka: Fukushima Medical University
Tetsuro Yokokawa: Fukushima Medical University
Kento Wada: Fukushima Medical University
Koki Ueda: Fukushima Medical University
Koichi Sugimoto: Fukushima Medical University
Keiji Minakawa: Fukushima Medical University
Kazuhiko Nakazato: Fukushima Medical University
Takafumi Ishida: Fukushima Medical University
Motohiko Oshima: The Institute of Medical Science, The University of Tokyo
Shuhei Koide: The Institute of Medical Science, The University of Tokyo
Kotaro Shide: University of Miyazaki
Kazuya Shimoda: University of Miyazaki
Atsushi Iwama: The Institute of Medical Science, The University of Tokyo
Kazuhiko Ikeda: Fukushima Medical University
Yasuchika Takeishi: Fukushima Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by pulmonary arterial remodeling. Clonal somatic mutations including JAK2V617F, the most frequent driver mutation among myeloproliferative neoplasms, have recently been identified in healthy individuals without hematological disorders. Here, we reveal that clonal hematopoiesis with JAK2V617F exacerbates PH and pulmonary arterial remodeling in mice. JAK2V617F-expressing neutrophils specifically accumulate in pulmonary arterial regions, accompanied by increases in neutrophil-derived elastase activity and chemokines in chronic hypoxia-exposed JAK2V617F transgenic (JAK2V617F) mice, as well as recipient mice transplanted with JAK2V617F bone marrow cells. JAK2V617F progressively upregulates Acvrl1 (encoding ALK1) during the differentiation from bone marrow stem/progenitor cells peripherally into mature neutrophils of pulmonary arterial regions. JAK2V617F-mediated STAT3 phosphorylation upregulates ALK1-Smad1/5/8 signaling. ALK1/2 inhibition completely prevents the development of PH in JAK2V617F mice. Finally, our prospective clinical study identified JAK2V617F-positive clonal hematopoiesis is more common in PH patients than in healthy subjects. These findings indicate that clonal hematopoiesis with JAK2V617F causally leads to PH development associated with ALK1 upregulation.

Date: 2021
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DOI: 10.1038/s41467-021-26435-0

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