{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:02:54Z","timestamp":1785816174440,"version":"3.56.0"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K17358"],"award-info":[{"award-number":["19K17358"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["17935423"],"award-info":[{"award-number":["17935423"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"crossref","award":["JPMJCR18S4"],"award-info":[{"award-number":["JPMJCR18S4"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16K10026"],"award-info":[{"award-number":["16K10026"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19188198"],"award-info":[{"award-number":["19188198"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["17935423"],"award-info":[{"award-number":["17935423"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["17935423"],"award-info":[{"award-number":["17935423"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Children with Down syndrome (DS) are susceptible to two blood disorders, transient abnormal myelopoiesis (TAM) and Down syndrome-associated acute megakaryocytic leukemia (DS-AMKL). Mutations in <jats:italic>GATA binding protein 1<\/jats:italic> (<jats:italic>GATA1<\/jats:italic>) have been identified as the cause of these diseases, and the expression levels of the resulting protein, short-form GATA1 (GATA1s), are known to correlate with the severity of TAM. On the other hand, despite the presence of <jats:italic>GATA1<\/jats:italic> mutations in almost all cases of DS-AMKL, the incidence of DS-AMKL in TAM patients is inversely correlated with the expression of GATA1s. This discovery has required the need to clarify the role of GATA1s in generating the cells of origin linked to the risk of both diseases. Focusing on this point, we examined the characteristics of <jats:italic>GATA1<\/jats:italic> mutant trisomy-21 pluripotent stem cells transfected with a doxycycline (Dox)-inducible GATA1s expression cassette in a stepwise hematopoietic differentiation protocol. We found that higher GATA1s expression significantly reduced commitment into the megakaryocytic lineage at the early hematopoietic progenitor cell (HPC) stage, but once committed, the effect was reversed in progenitor cells and acted to maintain the progenitors. These differentiation stage-dependent reversal effects were in contrast to the results of myeloid lineage, where GATA1s simply sustained and increased the number of immature myeloid cells. These results suggest that although <jats:italic>GATA1<\/jats:italic> mutant cells cause the increase in myeloid and megakaryocytic progenitors regardless of the intensity of GATA1s expression, the pathways vary with the expression level. This study provides experimental support for the paradoxical clinical features of <jats:italic>GATA1<\/jats:italic> mutations in the two diseases.<\/jats:p>","DOI":"10.1371\/journal.pone.0247595","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T17:31:35Z","timestamp":1617039095000},"page":"e0247595","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pluripotent stem cell model of early hematopoiesis in Down syndrome reveals quantitative effects of short-form GATA1 protein on lineage specification"],"prefix":"10.1371","volume":"16","author":[{"given":"Shiori","family":"Matsuo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Nishinaka-Arai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Kazuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuo","family":"Oshimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsutoshi","family":"Nakahata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6412-2686","authenticated-orcid":true,"given":"Akira","family":"Niwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumu K.","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"issue":"12","key":"pone.0247595.ref001","doi-asserted-by":"crossref","first-page":"4606","DOI":"10.1182\/blood-2005-06-2448","article-title":"A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children\u2019s Oncology Group (COG) study POG-9481","volume":"107","author":"GV Massey","year":"2006","journal-title":"Blood"},{"issue":"6","key":"pone.0247595.ref002","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1182\/blood-2007-01-069542","article-title":"Incidence and clinical implications of GATA1 mutations in newborns with Down syndrome","volume":"110","author":"SR Pine","year":"2007","journal-title":"Blood"},{"issue":"6","key":"pone.0247595.ref003","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1182\/blood-2007-10-118810","article-title":"Treatment and prognostic impact of transient leukemia in neonates with Down syndrome","volume":"111","author":"JH Klusmann","year":"2008","journal-title":"Blood"},{"issue":"4","key":"pone.0247595.ref004","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1111\/j.1365-2141.2008.07231.x","article-title":"Risk factors for early death in neonates with Down syndrome and transient leukaemia","volume":"142","author":"H Muramatsu","year":"2008","journal-title":"British journal of haematology"},{"issue":"26","key":"pone.0247595.ref005","doi-asserted-by":"crossref","first-page":"6752","DOI":"10.1182\/blood-2011-04-350017","article-title":"Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children\u2019s Oncology Group Study A2971","volume":"118","author":"AS Gamis","year":"2011","journal-title":"Blood"},{"issue":"5","key":"pone.0247595.ref006","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s11899-016-0338-x","article-title":"Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update","volume":"11","author":"N Bhatnagar","year":"2016","journal-title":"Current hematologic malignancy reports"},{"issue":"11","key":"pone.0247595.ref007","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1038\/ng.2759","article-title":"The landscape of somatic mutations in Down syndrome-related myeloid disorders","volume":"45","author":"K Yoshida","year":"2013","journal-title":"Nature genetics"},{"issue":"24","key":"pone.0247595.ref008","doi-asserted-by":"crossref","first-page":"3908","DOI":"10.1182\/blood-2013-07-515148","article-title":"GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia","volume":"122","author":"I Roberts","year":"2013","journal-title":"Blood"},{"issue":"1","key":"pone.0247595.ref009","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1365-2141.2009.07789.x","article-title":"Acute megakaryoblastic leukaemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: a multi-step model of myeloid leukaemogenesis","volume":"147","author":"A Roy","year":"2009","journal-title":"British journal of haematology"},{"issue":"1","key":"pone.0247595.ref010","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/ng955","article-title":"Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome","volume":"32","author":"J Wechsler","year":"2002","journal-title":"Nature genetics"},{"issue":"11","key":"pone.0247595.ref011","doi-asserted-by":"crossref","first-page":"4298","DOI":"10.1182\/blood-2002-12-3904","article-title":"Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis","volume":"101","author":"G Mundschau","year":"2003","journal-title":"Blood"},{"issue":"11","key":"pone.0247595.ref012","doi-asserted-by":"crossref","first-page":"4301","DOI":"10.1182\/blood-2003-01-0013","article-title":"GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome","volume":"101","author":"JK Hitzler","year":"2003","journal-title":"Blood"},{"issue":"3","key":"pone.0247595.ref013","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1182\/blood-2002-11-3599","article-title":"Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21","volume":"102","author":"L Rainis","year":"2003","journal-title":"Blood"},{"issue":"7","key":"pone.0247595.ref014","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1182\/blood-2003-10-3383","article-title":"Natural history of GATA1 mutations in Down syndrome","volume":"103","author":"M Ahmed","year":"2004","journal-title":"Blood"},{"issue":"4","key":"pone.0247595.ref015","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1046\/j.1365-2141.2002.03756.x","article-title":"Acquired trisomy 21 and distinct clonal evolution in acute megakaryoblastic leukaemia in young monozygotic twins","volume":"118","author":"B Stark","year":"2002","journal-title":"British journal of haematology"},{"issue":"1","key":"pone.0247595.ref016","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1182\/blood-2003-09-3219","article-title":"Fetal origin of the GATA1 mutation in identical twins with transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down syndrome","volume":"103","author":"A Shimada","year":"2004","journal-title":"Blood"},{"issue":"6265","key":"pone.0247595.ref017","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/344444a0","article-title":"Expression of an erythroid transcription factor in megakaryocytic and mast cell lineages","volume":"344","author":"DI Martin","year":"1990","journal-title":"Nature"},{"issue":"6265","key":"pone.0247595.ref018","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/344447a0","article-title":"Megakaryocytic and erythrocytic lineages share specific transcription factors","volume":"344","author":"PH Romeo","year":"1990","journal-title":"Nature"},{"issue":"11","key":"pone.0247595.ref019","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1101\/gad.4.11.1886","article-title":"Transcriptional activation and DNA binding by the erythroid factor GF-1\/NF-E1\/Eryf 1","volume":"4","author":"DI Martin","year":"1990","journal-title":"Genes & development"},{"issue":"6306","key":"pone.0247595.ref020","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/349257a0","article-title":"Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1","volume":"349","author":"L Pevny","year":"1991","journal-title":"Nature"},{"issue":"3","key":"pone.0247595.ref021","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1182\/blood.V80.3.575.575","article-title":"GATA-binding transcription factors in hematopoietic cells","volume":"80","author":"SH Orkin","year":"1992","journal-title":"Blood"},{"issue":"2","key":"pone.0247595.ref022","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1128\/MCB.15.2.634","article-title":"The C-terminal zinc finger of GATA-1 or GATA-2 is sufficient to induce megakaryocytic differentiation of an early myeloid cell line","volume":"15","author":"JE Visvader","year":"1995","journal-title":"Mol Cell Biol"},{"issue":"21","key":"pone.0247595.ref023","doi-asserted-by":"crossref","first-page":"9623","DOI":"10.1073\/pnas.92.21.9623","article-title":"Transcription factor GATA-1 permits survival and maturation of erythroid precursors by preventing apoptosis","volume":"92","author":"MJ Weiss","year":"1995","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"22","key":"pone.0247595.ref024","doi-asserted-by":"crossref","first-page":"12355","DOI":"10.1073\/pnas.93.22.12355","article-title":"Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1","volume":"93","author":"Y Fujiwara","year":"1996","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"13","key":"pone.0247595.ref025","doi-asserted-by":"crossref","first-page":"3965","DOI":"10.1093\/emboj\/16.13.3965","article-title":"A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development","volume":"16","author":"RA Shivdasani","year":"1997","journal-title":"EMBO J"},{"issue":"9","key":"pone.0247595.ref026","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1182\/blood.V93.9.2867.409k24_2867_2875","article-title":"Consequences of GATA-1 deficiency in megakaryocytes and platelets","volume":"93","author":"P Vyas","year":"1999","journal-title":"Blood"},{"issue":"18","key":"pone.0247595.ref027","doi-asserted-by":"crossref","first-page":"5250","DOI":"10.1093\/emboj\/20.18.5250","article-title":"In vivo requirements for GATA-1 functional domains during primitive and definitive erythropoiesis","volume":"20","author":"R Shimizu","year":"2001","journal-title":"EMBO J"},{"issue":"8","key":"pone.0247595.ref028","doi-asserted-by":"crossref","first-page":"2960","DOI":"10.1182\/blood-2003-02-0390","article-title":"Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome","volume":"102","author":"G Xu","year":"2003","journal-title":"Blood"},{"issue":"22","key":"pone.0247595.ref029","doi-asserted-by":"crossref","first-page":"4631","DOI":"10.1182\/blood-2010-05-282426","article-title":"Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia","volume":"116","author":"R Kanezaki","year":"2010","journal-title":"Blood"},{"issue":"4","key":"pone.0247595.ref030","doi-asserted-by":"crossref","first-page":"333","DOI":"10.5966\/sctm.2013-0172","article-title":"Pluripotent cell models of fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors","volume":"4","author":"NM Suzuki","year":"2015","journal-title":"Stem Cells Transl Med"},{"issue":"376","key":"pone.0247595.ref031","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aah5645","article-title":"Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors","volume":"9","author":"S Doulatov","year":"2017","journal-title":"Sci Transl Med"},{"key":"pone.0247595.ref032","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.exphem.2019.01.005","article-title":"Application of induced pluripotent stem cells to primary immunodeficiency diseases","volume":"71","author":"P Karagiannis","year":"2019","journal-title":"Exp Hematol"},{"key":"pone.0247595.ref033","doi-asserted-by":"crossref","first-page":"6136","DOI":"10.1038\/srep06136","article-title":"Down syndrome-associated haematopoiesis abnormalities created by chromosome transfer and genome editing technologies","volume":"4","author":"Y Kazuki","year":"2014","journal-title":"Scientific reports"},{"issue":"3","key":"pone.0247595.ref034","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1172\/JCI75714","article-title":"Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus","volume":"125","author":"M Byrska-Bishop","year":"2015","journal-title":"The Journal of clinical investigation"},{"issue":"6","key":"pone.0247595.ref035","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1016\/j.celrep.2016.04.031","article-title":"Systematic Cellular Disease Models Reveal Synergistic Interaction of Trisomy 21 and GATA1 Mutations in Hematopoietic Abnormalities","volume":"15","author":"K Banno","year":"2016","journal-title":"Cell reports"},{"key":"pone.0247595.ref036","article-title":"Down syndrome-related transient abnormal myelopoiesis is attributed to a specific erythro-megakaryocytic subpopulation with GATA1 mutation","author":"Y Nishinaka-Arai","year":"2020","journal-title":"Haematologica"},{"issue":"4","key":"pone.0247595.ref037","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.stem.2016.01.022","article-title":"CRISPR Interference Efficiently Induces Specific and Reversible Gene Silencing in Human iPSCs","volume":"18","author":"MA Mandegar","year":"2016","journal-title":"Cell stem cell"},{"issue":"1","key":"pone.0247595.ref038","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.celrep.2016.03.001","article-title":"Rapid Protein Depletion in Human Cells by Auxin-Inducible Degron Tagging with Short Homology Donors","volume":"15","author":"T Natsume","year":"2016","journal-title":"Cell reports"},{"key":"pone.0247595.ref039","doi-asserted-by":"crossref","first-page":"35680","DOI":"10.1038\/srep35680","article-title":"Laminin-guided highly efficient endothelial commitment from human pluripotent stem cells","volume":"6","author":"R Ohta","year":"2016","journal-title":"Scientific reports"},{"issue":"6","key":"pone.0247595.ref040","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1016\/j.stemcr.2018.04.004","article-title":"Pluripotent Stem Cell Model of Nakajo-Nishimura Syndrome Untangles Proinflammatory Pathways Mediated by Oxidative Stress","volume":"10","author":"F Honda-Ozaki","year":"2018","journal-title":"Stem Cell Reports"},{"issue":"6","key":"pone.0247595.ref041","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/ng1566","article-title":"Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1","volume":"37","author":"Z Li","year":"2005","journal-title":"Nature genetics"},{"issue":"4","key":"pone.0247595.ref042","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1182\/blood-2005-02-0551","article-title":"Differential requirements for the activation domain and FOG-interaction surface of GATA-1 in megakaryocyte gene expression and development","volume":"106","author":"AG Muntean","year":"2005","journal-title":"Blood"},{"issue":"6","key":"pone.0247595.ref043","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1038\/leu.2013.373","article-title":"GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia","volume":"28","author":"A Maroz","year":"2014","journal-title":"Leukemia"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247595","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T17:32:23Z","timestamp":1617039143000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247595"}},"subtitle":[],"editor":[{"given":"Johnson","family":"Rajasingh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,3,29]]},"references-count":43,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0247595","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,29]]}}}