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

被引:37
作者
Kimishima, Yusuke [1 ]
Misaka, Tomofumi [1 ,2 ]
Yokokawa, Tetsuro [1 ,3 ]
Wada, Kento [1 ]
Ueda, Koki [4 ]
Sugimoto, Koichi [1 ,3 ]
Minakawa, Keiji [4 ]
Nakazato, Kazuhiko [1 ]
Ishida, Takafumi [1 ]
Oshima, Motohiko [5 ]
Koide, Shuhei [5 ]
Shide, Kotaro [6 ]
Shimoda, Kazuya [6 ]
Iwama, Atsushi [5 ]
Ikeda, Kazuhiko [4 ]
Takeishi, Yasuchika [1 ]
机构
[1] Fukushima Med Univ, Dept Cardiovasc Med, Fukushima, Japan
[2] Fukushima Med Univ, Dept Adv Cardiac Therapeut, Fukushima, Japan
[3] Fukushima Med Univ, Dept Pulm Hypertens, Fukushima, Japan
[4] Fukushima Med Univ, Dept Blood Transfus & Transplantat Immunol, Fukushima, Japan
[5] Univ Tokyo, Ctr Stem Cell Biol & Regenerat Med, Inst Med Sci, Div Stem Cell & Mol Med, Tokyo, Japan
[6] Univ Miyazaki, Dept Gastroenterol & Hematol, Miyazaki, Japan
关键词
MYELOPROLIFERATIVE NEOPLASMS; MICE; RUXOLITINIB; DISEASE; ASSOCIATION; DEFICIENCY; MUTATION; OUTCOMES; THERAPY; REVEAL;
D O I
10.1038/s41467-021-26435-0
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 (JAK2(V617F)) mice, as well as recipient mice transplanted with JAK2(V617F) 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 JAK2(V617F) 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. Pulmonary hypertension is characterized by increased pulmonary arterial pressure, driven in part by inflammatory infiltrates. Here, the authors show that in mice, transgenic expression of mutant JAK2 leads to clonal hematopoiesis and lung accumulation of elastase- and cytokine-expressing neutrophils, and that the phenotype can be reversed by ALK1 inhibition.
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页数:18
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