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In addition to full-length GATA1, there is an GATA1 isoform, GATA1s, that lacks the amino-terminal transactivation domain. Somatic <jats:italic>GATA1<\/jats:italic> mutations that lead to the exclusive production of GATA1s appear to be necessary and sufficient for the development of a preleukemic condition called transient myeloproliferative disorder (TMD) in Down syndrome newborns. Subsequent clonal evolution among latent TMD blasts leads to the development of acute megakaryoblastic leukemia (AMKL). We originally established transgenic mice that express only GATA1s, which exhibit hyperproliferation of immature megakaryocytes, thus mimicking human TMD; however, these mice never developed AMKL. Here, we report that transgenic mice expressing moderate levels of GATA1s, i.e., roughly comparable levels to endogenous GATA1, were prone to develop AMKL in young adults. However, when GATA1s is expressed at levels significantly exceeding that of endogenous GATA1, the development of leukemia was restrained in a dose dependent manner. If the transgenic increase of GATA1s in progenitors remains small, GATA1s supports the terminal maturation of megakaryocyte progenitors insufficiently, and consequently the progenitors persisted, leading to an increased probability for acquisition of additional genetic modifications. In contrast, more abundant GATA1s expression compensates for this maturation block, enabling megakaryocytic progenitors to fully differentiate. This study provides evidence for the clinical observation that the abundance of GATA1s correlates well with the progression to AMKL in Down syndrome.<\/jats:p>","DOI":"10.1186\/s40164-024-00492-9","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T07:02:14Z","timestamp":1708930934000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The abundance of the short GATA1 isoform affects megakaryocyte differentiation and leukemic predisposition in mice"],"prefix":"10.1186","volume":"13","author":[{"given":"Daishi","family":"Ishihara","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Hasegawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ikuo","family":"Hirano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James Douglas","family":"Engel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ritsuko","family":"Shimizu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,2,26]]},"reference":[{"key":"492_CR1","doi-asserted-by":"publisher","first-page":"21439","DOI":"10.1074\/jbc.M112.370437","volume":"287","author":"H Kaneko","year":"2012","unstructured":"Kaneko H, Kobayashi E, Yamamoto M, Shimizu R. N- and C-terminal transactivation domains of GATA1 protein coordinate hematopoietic program. J Biol Chem. 2012;287:21439\u201349.","journal-title":"J Biol Chem"},{"key":"492_CR2","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1038\/ng.2759","volume":"45","author":"K Yoshida","year":"2013","unstructured":"Yoshida K, Toki T, Okuno Y, et al. The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat Genet. 2013;45:1293\u20139.","journal-title":"Nat Genet"},{"key":"492_CR3","doi-asserted-by":"crossref","unstructured":"Shimizu R, Yamamoto M. Leukemogenesis in Down syndrome. In: Day S, ed. Health Problems in Down Syndrome: Rijeka, Croatia, InTech; 2015. Available at: http:\/\/www.intechopen.com\/books\/health-problems-in-down-syndrome\/leukemogenesis-in-down-syndrome.","DOI":"10.5772\/60598"},{"key":"492_CR4","doi-asserted-by":"publisher","first-page":"4631","DOI":"10.1182\/blood-2010-05-282426","volume":"116","author":"R Kanezaki","year":"2010","unstructured":"Kanezaki R, Toki T, Terui K, et al. Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia. Blood. 2010;116:4631\u20138.","journal-title":"Blood"},{"key":"492_CR5","doi-asserted-by":"crossref","unstructured":"Shimizu R, Takahashi S, Ohneda K, Engel JD, Yamamoto M. In vivo requirements for GATA-1 functional domains during primitive and definitive erythropoiesis. Embo J 2001;20:5250-60.","DOI":"10.1093\/emboj\/20.18.5250"},{"key":"492_CR6","doi-asserted-by":"publisher","first-page":"12611","DOI":"10.1074\/jbc.272.19.12611","volume":"272","author":"S Takahashi","year":"1997","unstructured":"Takahashi S, Onodera K, Motohashi H, et al. Arrest in primitive erythroid cell development caused by promoter- specific disruption of the GATA-1 gene. J Biol Chem. 1997;272:12611\u20135.","journal-title":"J Biol Chem"},{"key":"492_CR7","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1111\/j.1365-2443.2009.01338.x","volume":"14","author":"R Shimizu","year":"2009","unstructured":"Shimizu R, Kobayashi E, Engel JD, Yamamoto M. Induction of hyperproliferative fetal megakaryopoiesis by an N-terminally truncated GATA1 mutant. Genes Cells. 2009;14:1119\u201331.","journal-title":"Genes Cells"},{"key":"492_CR8","doi-asserted-by":"publisher","first-page":"e0247595","DOI":"10.1371\/journal.pone.0247595","volume":"16","author":"S Matsuo","year":"2021","unstructured":"Matsuo S, Nishinaka-Arai Y, Kazuki Y, et al. Pluripotent stem cell model of early hematopoiesis in Down syndrome reveals quantitative effect of short-form GATA1 protein on lineage specification. PLoS ONE. 2021;16:e0247595.","journal-title":"PLoS ONE"},{"key":"492_CR9","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/nrc2348","volume":"8","author":"R Shimizu","year":"2008","unstructured":"Shimizu R, Engel JD, Yamamoto M. GATA1-related leukaemias. Nat Rev Cancer. 2008;8:279\u201387.","journal-title":"Nat Rev Cancer"},{"key":"492_CR10","doi-asserted-by":"publisher","first-page":"10814","DOI":"10.1128\/MCB.24.24.10814-10825.2004","volume":"24","author":"R Shimizu","year":"2004","unstructured":"Shimizu R, Kuroha T, Ohneda O, et al. Leukemogenesis caused by incapacitated GATA-1 function. Mol Cell Biol. 2004;24:10814\u201325.","journal-title":"Mol Cell Biol"},{"key":"492_CR11","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1093\/oxfordjournals.jbchem.a022570","volume":"127","author":"X Pan","year":"2000","unstructured":"Pan X, Minegishi N, Harigae H, et al. Identification of human GATA-2 gene distal IS exon and its expression in hematopoietic stem cell fractions. J Biochem. 2000;127:105\u201312.","journal-title":"J Biochem"},{"key":"492_CR12","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.1111\/cas.12007","volume":"103","author":"R Shimizu","year":"2012","unstructured":"Shimizu R, Yamamoto M. Contribution of GATA1 dysfunction to multi-step leukemogenesis. Cancer Sci. 2012;103:2039\u201344.","journal-title":"Cancer Sci"},{"key":"492_CR13","doi-asserted-by":"publisher","first-page":"466","DOI":"10.5858\/arpa.2018-0526-OA","volume":"144","author":"KJ Mast","year":"2020","unstructured":"Mast KJ, Taub JW, Alonzo TA, et al. Pathologic features of Down syndrome myelodysplastic syndrome and acute myeloid leukemia: a report from the children\u2019s Oncology Group Protocol AAML0431. Arch Pathol Lab Med. 2020;144:466\u201372.","journal-title":"Arch Pathol Lab Med"}],"container-title":["Experimental Hematology &amp; Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-024-00492-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40164-024-00492-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-024-00492-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T07:04:02Z","timestamp":1708931042000},"score":1,"resource":{"primary":{"URL":"https:\/\/ehoonline.biomedcentral.com\/articles\/10.1186\/s40164-024-00492-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,26]]},"references-count":13,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["492"],"URL":"https:\/\/doi.org\/10.1186\/s40164-024-00492-9","relation":{},"ISSN":["2162-3619"],"issn-type":[{"type":"electronic","value":"2162-3619"}],"subject":[],"published":{"date-parts":[[2024,2,26]]},"assertion":[{"value":"11 November 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal studies were conducted in accordance with guidelines approved by the Institutional Animal Experiment Committee of the Tohoku University.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participant"}},{"value":"All authors approved the manuscript and the submission.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing financial interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"24"}}