{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:18:51Z","timestamp":1790691531134,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,5,9]],"date-time":"2018-05-09T00:00:00Z","timestamp":1525824000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15K15368"],"award-info":[{"award-number":["15K15368"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16J11017"],"award-info":[{"award-number":["16J11017"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16K09859"],"award-info":[{"award-number":["16K09859"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K16195"],"award-info":[{"award-number":["17K16195"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17H04211"],"award-info":[{"award-number":["17H04211"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Somatic mutations in the <jats:italic>calreticulin<\/jats:italic> (<jats:italic><jats:styled-content style=\"fixed-case\">CALR<\/jats:styled-content><\/jats:italic>) gene have been found in most patients with <jats:italic><jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>2<\/jats:italic>\u2010 and <jats:italic><jats:styled-content style=\"fixed-case\">MPL<\/jats:styled-content><\/jats:italic>\u2010unmutated Philadelphia chromosome\u2010negative myeloproliferative neoplasms (<jats:styled-content style=\"fixed-case\">MPN<\/jats:styled-content>s). It has recently been shown that mutant <jats:styled-content style=\"fixed-case\">CALR<\/jats:styled-content> constitutively activates the thrombopoietin receptor <jats:styled-content style=\"fixed-case\">MPL<\/jats:styled-content> and, thus, plays a causal role in the development of <jats:styled-content style=\"fixed-case\">MPN<\/jats:styled-content>s. However, the roles of mutant <jats:styled-content style=\"fixed-case\">CALR<\/jats:styled-content> in human haematopoietic cell differentiation remain predominantly elusive. To examine the impact of the 5\u2010base insertion mutant <jats:italic><jats:styled-content style=\"fixed-case\">CALR<\/jats:styled-content><\/jats:italic> gene (Ins5) on haematopoietic cell differentiation, we generated induced pluripotent stem cells from an essential thrombocythaemia (<jats:styled-content style=\"fixed-case\">ET<\/jats:styled-content>) patient harbouring a <jats:italic><jats:styled-content style=\"fixed-case\">CALR<\/jats:styled-content><\/jats:italic>\u2010Ins5 mutation and from a healthy individual (<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>). Megakaryopoiesis was more prominent in Ins5\u2010haematopoietic progenitor cells (Ins5\u2010<jats:styled-content style=\"fixed-case\">HPC<\/jats:styled-content>s) than in <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">HPC<\/jats:styled-content>s, implying that the system recapitulates megakaryocytosis observed in the bone marrow of <jats:italic><jats:styled-content style=\"fixed-case\">CALR<\/jats:styled-content><\/jats:italic>\u2010mutant <jats:styled-content style=\"fixed-case\">ET<\/jats:styled-content> patients. Ins5\u2010<jats:styled-content style=\"fixed-case\">HPC<\/jats:styled-content>s exhibited elevated expression levels of <jats:italic><jats:styled-content style=\"fixed-case\">GATA<\/jats:styled-content>1<\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">GATA<\/jats:styled-content>2,<\/jats:italic> suggesting a premature commitment to megakaryocytic differentiation in progenitor cells. We also demonstrated that 3\u2010hydroxy anagrelide markedly perturbed megakaryopoiesis, but not erythropoiesis. Collectively, we established an <jats:italic>in\u00a0vitro<\/jats:italic> model system that recapitulates megakaryopoiesis caused by mutant <jats:italic><jats:styled-content style=\"fixed-case\">CALR<\/jats:styled-content><\/jats:italic>. This system can be used to validate therapeutic compounds for <jats:styled-content style=\"fixed-case\">MPN<\/jats:styled-content> patients harbouring <jats:italic><jats:styled-content style=\"fixed-case\">CALR<\/jats:styled-content><\/jats:italic> mutations and in detailed studies on mutant <jats:styled-content style=\"fixed-case\">CALR<\/jats:styled-content> in human haematological cell differentiation.<\/jats:p>","DOI":"10.1111\/bjh.15266","type":"journal-article","created":{"date-parts":[[2018,5,9]],"date-time":"2018-05-09T17:12:50Z","timestamp":1525885970000},"page":"791-802","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Skewed megakaryopoiesis in human induced pluripotent stem\u00a0cell\u2010derived haematopoietic progenitor cells harbouring calreticulin mutations"],"prefix":"10.1111","volume":"181","author":[{"given":"Hiraku","family":"Takei","sequence":"first","affiliation":[{"name":"Department of Haematology Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Edahiro","sequence":"additional","affiliation":[{"name":"Department of Haematology Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Mano","sequence":"additional","affiliation":[{"name":"Department of Haematology Juntendo University Graduate School of Medicine Tokyo Japan"},{"name":"Department of Life Science and Medical Bioscience Waseda University Graduate School Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nami","family":"Masubuchi","sequence":"additional","affiliation":[{"name":"Department of Haematology Juntendo University Graduate School of Medicine Tokyo Japan"},{"name":"Research Institute for Disease of Old Age Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihisa","family":"Mizukami","sequence":"additional","affiliation":[{"name":"Department of Haematology Juntendo University Graduate School of Medicine Tokyo Japan"},{"name":"Centre for Genomic and Regenerative Medicine Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misa","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Haematology Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soji","family":"Morishita","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine and Stem Cell Regulation Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyohei","family":"Misawa","sequence":"additional","affiliation":[{"name":"Department of Haematology Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6156-4211","authenticated-orcid":false,"given":"Tomonori","family":"Ochiai","sequence":"additional","affiliation":[{"name":"Department of Haematology Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Tsuneda","sequence":"additional","affiliation":[{"name":"Department of Life Science and Medical Bioscience Waseda University Graduate School Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Endo","sequence":"additional","affiliation":[{"name":"Department of Clinical Application CiRA, Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sou","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Clinical Application CiRA, Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Eto","sequence":"additional","affiliation":[{"name":"Department of Clinical Application CiRA, Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akimichi","family":"Ohsaka","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine and Stem Cell Regulation Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marito","family":"Araki","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine and Stem Cell Regulation Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1880-9126","authenticated-orcid":false,"given":"Norio","family":"Komatsu","sequence":"additional","affiliation":[{"name":"Department of Haematology Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2010.03970.x"},{"key":"e_1_2_8_3_1","first-page":"149","article-title":"Interleukin\u20106 and erythropoietin act as direct potentiators and inducers of in\u00a0vitro cytoplasmic process formation on purified mouse megakaryocytes","volume":"22","author":"An E.","year":"1994","journal-title":"Experimental Hematology"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-09-671172"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-11-681932"},{"key":"e_1_2_8_6_1","first-page":"1207","article-title":"A standardized endogenous megakaryocytic erythroid colony assay for the diagnosis of essential thrombocythemia","volume":"89","author":"Dobo I.","year":"2004","journal-title":"Haematologica"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-014-1567-1"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-15-1434"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12850"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2012.0173"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.22.12355"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-07-443770"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2017.08.006"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2014.113845"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64721"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2014.03.010"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-472X(00)00553-1"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-017-2246-9"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112796"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408617"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2012.244"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1311347"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1986.tb04116.x"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031556"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-11-679571"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1089\/152581601750289000"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1312542"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1591"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1293"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2015.11.010"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V93.2.488"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1019524108"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-11-538983"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-11-539098"},{"key":"e_1_2_8_35_1","first-page":"1028","article-title":"Human erythropoietin stimulates murine megakaryopoiesis in serum\u2010free culture","volume":"15","author":"Sakaguchi M.","year":"1987","journal-title":"Experimental Hematology"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-016-2006-2"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0074257"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.308"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2014.115113"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-07-2740"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0057633"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-307-3_15"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-10-117622"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100844"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-04-083501"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.23743"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.302"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.10.3636"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-695940"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706341"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3733"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0120841"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-04-217406"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1545"}],"container-title":["British Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbjh.15266","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bjh.15266","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T19:16:05Z","timestamp":1694286965000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bjh.15266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,9]]},"references-count":53,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2018,6]]}},"alternative-id":["10.1111\/bjh.15266"],"URL":"https:\/\/doi.org\/10.1111\/bjh.15266","archive":["Portico"],"relation":{},"ISSN":["0007-1048","1365-2141"],"issn-type":[{"value":"0007-1048","type":"print"},{"value":"1365-2141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,9]]},"assertion":[{"value":"2017-12-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-02-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-05-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}