{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T19:37:04Z","timestamp":1783971424089,"version":"3.55.0"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T00:00:00Z","timestamp":1630886400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T00:00:00Z","timestamp":1630886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The MEXT\u2019s Promotion Plan for the Platform of Human Resource Development for Cancer Project"},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"JSPS KAKENHI Grants","award":["#20H03715"],"award-info":[{"award-number":["#20H03715"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A subset of essential thrombocythemia (ET) cases are negative for disease-defining mutations on <jats:italic>JAK2<\/jats:italic>, <jats:italic>MPL<\/jats:italic>, and <jats:italic>CALR<\/jats:italic> and defined as triple negative (TN). The lack of recurrent mutations in TN-ET patients makes its pathogenesis ambiguous. Here, we screened 483 patients with suspected ET in a single institution, centrally reviewed bone marrow specimens, and identified 23 TN-ET patients. Analysis of clinical records revealed that TN-ET patients were mostly young female, without a history of thrombosis or progression to secondary myelofibrosis and leukemia. Sequencing analysis and human androgen receptor assays revealed that the majority of TN-ET patients exhibited polyclonal hematopoiesis, suggesting a possibility of reactive thrombocytosis in TN-ET. However, the serum levels of thrombopoietin (TPO) and interleukin-6 in TN-ET patients were not significantly different from those in ET patients with canonical mutations and healthy individuals. Rather, CD34-positive cells from TN-ET patients showed a capacity to form megakaryocytic colonies, even in the absence of TPO. No signs of thrombocytosis were observed before TN-ET development, denying the possibility of hereditary thrombocytosis in TN-ET. Overall, these findings indicate that TN-ET is a distinctive disease entity associated with polyclonal hematopoiesis and is paradoxically caused by hematopoietic stem cells harboring a capacity for cell-autonomous megakaryopoiesis.<\/jats:p>","DOI":"10.1038\/s41598-021-97106-9","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T10:04:08Z","timestamp":1630922648000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia"],"prefix":"10.1038","volume":"11","author":[{"given":"Tadaaki","family":"Inano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marito","family":"Araki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soji","family":"Morishita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misa","family":"Imai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiko","family":"Kihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maho","family":"Okuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinjie","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Osaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Mano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Edahiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomonori","family":"Ochiai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyohei","family":"Misawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasutaka","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Komatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,6]]},"reference":[{"key":"97106_CR1","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1182\/blood-2016-10-695940","volume":"129","author":"W Vainchenker","year":"2017","unstructured":"Vainchenker, W. & Kralovics, R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood 129, 667\u2013679. https:\/\/doi.org\/10.1182\/blood-2016-10-695940 (2017).","journal-title":"Blood"},{"key":"97106_CR2","doi-asserted-by":"publisher","first-page":"2300","DOI":"10.1038\/leu.2014.148","volume":"28","author":"A Tefferi","year":"2014","unstructured":"Tefferi, A. et al. Calreticulin mutations and long-term survival in essential thrombocythemia. Leukemia 28, 2300\u20132303. https:\/\/doi.org\/10.1038\/leu.2014.148 (2014).","journal-title":"Leukemia"},{"key":"97106_CR3","doi-asserted-by":"publisher","first-page":"2379","DOI":"10.1056\/NEJMoa1311347","volume":"369","author":"T Klampfl","year":"2013","unstructured":"Klampfl, T. et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N. Engl. J. Med. 369, 2379\u20132390. https:\/\/doi.org\/10.1056\/NEJMoa1311347 (2013).","journal-title":"N. Engl. J. 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JAK2, CALR, and MPL mutation spectrum in Japanese patients with myeloproliferative neoplasms. Haematologica 100, e46-48. https:\/\/doi.org\/10.3324\/haematol.2014.115113 (2015).","journal-title":"Haematologica"},{"key":"97106_CR7","doi-asserted-by":"publisher","first-page":"2507","DOI":"10.1182\/blood-2014-05-579136","volume":"124","author":"A Tefferi","year":"2014","unstructured":"Tefferi, A. et al. 2014 Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 124, 2507\u20132513. https:\/\/doi.org\/10.1182\/blood-2014-05-579136 (2014) (quiz 2615).","journal-title":"Blood"},{"key":"97106_CR8","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1038\/leu.2014.138","volume":"28","author":"R Fu","year":"2014","unstructured":"Fu, R. et al. Analysis of calreticulin mutations in Chinese patients with essential thrombocythemia: Clinical implications in diagnosis, prognosis and treatment. Leukemia 28, 1912\u20131914. https:\/\/doi.org\/10.1038\/leu.2014.138 (2014).","journal-title":"Leukemia"},{"key":"97106_CR9","doi-asserted-by":"publisher","first-page":"1552","DOI":"10.1182\/blood-2013-11-538983","volume":"123","author":"G Rotunno","year":"2014","unstructured":"Rotunno, G. et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 123, 1552\u20131555. https:\/\/doi.org\/10.1182\/blood-2013-11-538983 (2014).","journal-title":"Blood"},{"key":"97106_CR10","doi-asserted-by":"publisher","first-page":"e463","DOI":"10.1038\/bcj.2016.75","volume":"6","author":"A Angona","year":"2016","unstructured":"Angona, A. et al. Molecular characterisation of triple negative essential thrombocythaemia patients by platelet analysis and targeted sequencing. 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Blood 127, 2391\u20132405. https:\/\/doi.org\/10.1182\/blood-2016-03-643544 (2016).","journal-title":"Blood"},{"key":"97106_CR25","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1007\/s12185-018-2421-7","volume":"107","author":"K Misawa","year":"2018","unstructured":"Misawa, K. et al. Mutational subtypes of JAK2 and CALR correlate with different clinical features in Japanese patients with myeloproliferative neoplasms. Int. J. Hematol. 107, 673\u2013680. https:\/\/doi.org\/10.1007\/s12185-018-2421-7 (2018).","journal-title":"Int. J. Hematol."},{"key":"97106_CR26","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1007\/s12185-014-1567-1","volume":"99","author":"Y Edahiro","year":"2014","unstructured":"Edahiro, Y. et al. JAK2V617F mutation status and allele burden in classical Ph-negative myeloproliferative neoplasms in Japan. Int. J. Hematol. 99, 625\u2013634. https:\/\/doi.org\/10.1007\/s12185-014-1567-1 (2014).","journal-title":"Int. J. 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