Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice
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 CRI...
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| Format: | Article |
| Language: | English |
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BMC
2021-03-01
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| Series: | Journal of Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13045-021-01064-8 |
| _version_ | 1818646745455788032 |
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| author | Keiji Minakawa Tetsuro Yokokawa Koki Ueda Osamu Nakajima Tomofumi Misaka Yusuke Kimishima Kento Wada Yusuke Tomita Saori Miura Yuka Sato Kosaku Mimura Koichi Sugimoto Kazuhiko Nakazato Kenneth E. Nollet Kazuei Ogawa Takayuki Ikezoe Yuko Hashimoto Yasuchika Takeishi Kazuhiko Ikeda |
| author_facet | Keiji Minakawa Tetsuro Yokokawa Koki Ueda Osamu Nakajima Tomofumi Misaka Yusuke Kimishima Kento Wada Yusuke Tomita Saori Miura Yuka Sato Kosaku Mimura Koichi Sugimoto Kazuhiko Nakazato Kenneth E. Nollet Kazuei Ogawa Takayuki Ikezoe Yuko Hashimoto Yasuchika Takeishi Kazuhiko Ikeda |
| author_sort | Keiji Minakawa |
| collection | DOAJ |
| description | 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 [Calr del10/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 (Calr ins2/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 Calr del10/WT mice, although PB cell counts were not different from those in BMT recipients from Calr WT/WT mice, Calr del10/WT BM-derived macrophages exhibited elevations of pSTAT3 and Endothelin-1 levels. Strikingly, BMT recipients from Calr del10/WT mice developed more severe pulmonary hypertension (PH)—which often arises as a comorbidity in patients with MPNs—than BMT recipients from Calr WT/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. |
| first_indexed | 2024-12-17T00:51:31Z |
| format | Article |
| id | doaj.art-a52a446c0dda4a20af5f7f461b6cd565 |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-12-17T00:51:31Z |
| publishDate | 2021-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-a52a446c0dda4a20af5f7f461b6cd5652022-12-21T22:09:46ZengBMCJournal of Hematology & Oncology1756-87222021-03-011411610.1186/s13045-021-01064-8Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in miceKeiji Minakawa0Tetsuro Yokokawa1Koki Ueda2Osamu Nakajima3Tomofumi Misaka4Yusuke Kimishima5Kento Wada6Yusuke Tomita7Saori Miura8Yuka Sato9Kosaku Mimura10Koichi Sugimoto11Kazuhiko Nakazato12Kenneth E. Nollet13Kazuei Ogawa14Takayuki Ikezoe15Yuko Hashimoto16Yasuchika Takeishi17Kazuhiko Ikeda18Department of Blood Transfusion and Transplantation Immunology, School of Medicine, Fukushima Medical UniversityDepartment of Cardiovascular Medicine, School of Medicine, Fukushima Medical UniversityDepartment of Blood Transfusion and Transplantation Immunology, School of Medicine, Fukushima Medical UniversityCenter for Molecular Genetics, Yamagata UniversityDepartment of Cardiovascular Medicine, School of Medicine, Fukushima Medical UniversityDepartment of Cardiovascular Medicine, School of Medicine, Fukushima Medical UniversityDepartment of Cardiovascular Medicine, School of Medicine, Fukushima Medical UniversityDepartment of Cardiovascular Medicine, School of Medicine, Fukushima Medical UniversityDepartment of Blood Transfusion and Transplantation Immunology, School of Medicine, Fukushima Medical UniversityDepartment of Blood Transfusion and Transplantation Immunology, School of Medicine, Fukushima Medical UniversityDepartment of Blood Transfusion and Transplantation Immunology, School of Medicine, Fukushima Medical UniversityDepartment of Cardiovascular Medicine, School of Medicine, Fukushima Medical UniversityDepartment of Cardiovascular Medicine, School of Medicine, Fukushima Medical UniversityDepartment of Blood Transfusion and Transplantation Immunology, School of Medicine, Fukushima Medical UniversityDepartment of Hematology, School of Medicine, Fukushima Medical UniversityDepartment of Hematology, School of Medicine, Fukushima Medical UniversityDepartment of Diagnostic Pathology, School of Medicine, Fukushima Medical UniversityDepartment of Cardiovascular Medicine, School of Medicine, Fukushima Medical UniversityDepartment of Blood Transfusion and Transplantation Immunology, School of Medicine, Fukushima Medical UniversityAbstract 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 [Calr del10/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 (Calr ins2/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 Calr del10/WT mice, although PB cell counts were not different from those in BMT recipients from Calr WT/WT mice, Calr del10/WT BM-derived macrophages exhibited elevations of pSTAT3 and Endothelin-1 levels. Strikingly, BMT recipients from Calr del10/WT mice developed more severe pulmonary hypertension (PH)—which often arises as a comorbidity in patients with MPNs—than BMT recipients from Calr WT/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.https://doi.org/10.1186/s13045-021-01064-8CALRPulmonary hypertensionMyeloproliferative neoplasmsMacrophageEssential thrombocythemia |
| spellingShingle | Keiji Minakawa Tetsuro Yokokawa Koki Ueda Osamu Nakajima Tomofumi Misaka Yusuke Kimishima Kento Wada Yusuke Tomita Saori Miura Yuka Sato Kosaku Mimura Koichi Sugimoto Kazuhiko Nakazato Kenneth E. Nollet Kazuei Ogawa Takayuki Ikezoe Yuko Hashimoto Yasuchika Takeishi Kazuhiko Ikeda Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice Journal of Hematology & Oncology CALR Pulmonary hypertension Myeloproliferative neoplasms Macrophage Essential thrombocythemia |
| title | Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice |
| title_full | Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice |
| title_fullStr | Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice |
| title_full_unstemmed | Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice |
| title_short | Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice |
| title_sort | myeloproliferative neoplasm driving calr frameshift promotes the development of pulmonary hypertension in mice |
| topic | CALR Pulmonary hypertension Myeloproliferative neoplasms Macrophage Essential thrombocythemia |
| url | https://doi.org/10.1186/s13045-021-01064-8 |
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