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

Yusuke Kimishima,Atsushi Iwama,Tetsuro Yokokawa,Koichi Sugimoto,Motohiko Oshima,Koki Ueda,Kotaro Shide,Kazuya Shimoda,Kazuhiko Nakazato,Tomofumi Misaka,Kazuhiko Ikeda,Kento Wada,Keiji Minakawa,Takafumi Ishida,Yasuchika Takeishi,Shuhei Koide

doi:10.1038/s41467-021-26435-0

Yusuke Kimishima, Atsushi Iwama + Show 14 more

Open Access

https://doi.org/10.1038/s41467-021-26435-0

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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.

Highlights

Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by pulmonary arterial remodeling
We found that Right ventricular systolic pressure (RVSP) was significantly elevated in JAK2V617F mice compared to WT mice in response to continuous hypoxia (Fig. 1c) in line with the echocardiographic evaluation of pulmonary hemodynamics (Supplementary Fig. 2)
We found that even male JAK2V617F mice showed significant increases in RVSP and RV/LV + S compared to male WT mice 2 weeks after chronic hypoxia (Supplementary Fig. 4)

Summary

Introduction

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. 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. Recent advances in genetic analyses have led to the discovery of clonal hematopoiesis, whose hematopoietic stem/progenitor cells harbor somatic mutations in genes often mutated in myeloid cancers, including MPNs, in healthy individuals without any hematologic disorders[12,13]. We provide the evidence that clonal hematopoiesis with JAK2V617F plays causal roles in the development of PH with ALK1 upregulation in lung neutrophils

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