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Here, we generated knock-in mice with murine <jats:italic>Calr<\/jats:italic> exon 9 mimicking the human <jats:italic>CALR<\/jats:italic> mutations, using the CRISPR-Cas9 method. Knock-in mice with del10 [<jats:italic>Calr<\/jats:italic><jats:sup>del10\/WT (wild\u2212type)<\/jats:sup> mice] exhibited an ET phenotype with increases of peripheral blood (PB) platelets and leukocytes, and accumulation of megakaryocytes in bone marrow (BM), while those with ins2 (<jats:italic>Calr<\/jats:italic><jats:sup>ins2\/WT<\/jats:sup> mice) showed a slight splenic enlargement. Phosphorylated STAT3 (pSTAT3) was upregulated in BM cells of both knock-in mice. In BM transplantation (BMT) recipients from <jats:italic>Calr<\/jats:italic><jats:sup>del10\/WT<\/jats:sup> mice, although PB cell counts were not different from those in BMT recipients from <jats:italic>Calr<\/jats:italic><jats:sup>WT\/WT<\/jats:sup> mice, <jats:italic>Calr<\/jats:italic><jats:sup>del10\/WT<\/jats:sup> BM-derived macrophages exhibited elevations of pSTAT3 and Endothelin-1 levels. Strikingly, BMT recipients from <jats:italic>Calr<\/jats:italic><jats:sup>del10\/WT<\/jats:sup> mice developed more severe pulmonary hypertension (PH)\u2014which often arises as a comorbidity in patients with MPNs\u2014than BMT recipients from <jats:italic>Calr<\/jats:italic><jats:sup>WT\/WT<\/jats:sup> mice, with pulmonary arterial remodeling accompanied by an accumulation of donor-derived macrophages in response to chronic hypoxia. In conclusion, our murine model with the frameshifted murine <jats:italic>Calr<\/jats:italic> presented an ET phenotype analogous to human MPNs in molecular mechanisms and cardiovascular complications such as PH.<\/jats:p>","DOI":"10.1186\/s13045-021-01064-8","type":"journal-article","created":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T14:02:59Z","timestamp":1617112979000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice"],"prefix":"10.1186","volume":"14","author":[{"given":"Keiji","family":"Minakawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuro","family":"Yokokawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koki","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Nakajima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomofumi","family":"Misaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Kimishima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kento","family":"Wada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Tomita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Miura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosaku","family":"Mimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Sugimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Nakazato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth E.","family":"Nollet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuei","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Ikezoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuchika","family":"Takeishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5269-269X","authenticated-orcid":false,"given":"Kazuhiko","family":"Ikeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,30]]},"reference":[{"key":"1064_CR1","doi-asserted-by":"publisher","first-page":"2379","DOI":"10.1056\/NEJMoa1311347","volume":"369","author":"T Klampfl","year":"2013","unstructured":"Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379\u201390.","journal-title":"N Engl J Med"},{"key":"1064_CR2","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1161\/CIRCRESAHA.113.301141","volume":"115","author":"M Rabinovitch","year":"2014","unstructured":"Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115:165\u201375.","journal-title":"Circ Res"},{"key":"1064_CR3","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1182\/blood-2012-03-419275","volume":"120","author":"K Asosingh","year":"2012","unstructured":"Asosingh K, Farha S, Lichtin A, Graham B, George D, Aldred M, et al. Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension. 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All efforts were addressed to minimize suffering. All studies were approved by the Animal Study Committees of Fukushima Medical University (App. No. 245, 30086) and Yamagata University (App. No. 27-153, 28-113).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"T.Y.\u2019s and K.S.\u2019s department receives support from Janssen Pharmaceutical K.K., Japan. T.M.\u2019s department receives support from Fukuda Denshi Co., Ltd., Japan. These companies were not associated with the contents of this study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"52"}}