NDLI: Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice

Content Provider	Springer Nature : BioMed Central
Author	Minakawa, Keiji Yokokawa, Tetsuro Ueda, Koki Nakajima, Osamu Misaka, Tomofumi Kimishima, Yusuke Wada, Kento Tomita, Yusuke Miura, Saori Sato, Yuka Mimura, Kosaku Sugimoto, Koichi Nakazato, Kazuhiko Nollet, Kenneth E. Ogawa, Kazuei Ikezoe, Takayuki Hashimoto, Yuko Takeishi, Yasuchika Ikeda, Kazuhiko
Abstract	Frameshifts in the Calreticulin (CALR) exon 9 provide a recurrent driver mutation of essential thrombocythemia (ET) and primary myelofibrosis among myeloproliferative neoplasms (MPNs). Here, we generated knock-in mice with murine Calr exon 9 mimicking the human CALR mutations, using the CRISPR-Cas9 method. Knock-in mice with del10 [Calrdel10/WT (wild−type) 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 (Calrins2/WT 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 Calrdel10/WT mice, although PB cell counts were not different from those in BMT recipients from CalrWT/WT mice, Calrdel10/WT BM-derived macrophages exhibited elevations of pSTAT3 and Endothelin-1 levels. Strikingly, BMT recipients from Calrdel10/WT mice developed more severe pulmonary hypertension (PH)—which often arises as a comorbidity in patients with MPNs—than BMT recipients from CalrWT/WT 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 Calr presented an ET phenotype analogous to human MPNs in molecular mechanisms and cardiovascular complications such as PH.
Related Links	https://jhoonline.biomedcentral.com/counter/pdf/10.1186/s13045-021-01064-8.pdf
Ending Page	6
Page Count	6
Starting Page	1
File Format	HTM / HTML
ISSN	17568722
DOI	10.1186/s13045-021-01064-8
Journal	Journal of Hematology & Oncology
Issue Number	1
Volume Number	14
Language	English
Publisher	BioMed Central
Publisher Date	2021-03-30
Access Restriction	Open
Subject Keyword	Oncology Hematology Cancer Research CALR Pulmonary hypertension Myeloproliferative neoplasms Macrophage Essential thrombocythemia
Content Type	Text
Subject	Hematology Cancer Research Oncology Molecular Biology
Journal Impact Factor	29.9/2023
5-Year Journal Impact Factor	27.1/2023

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