{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:55:10Z","timestamp":1789520110062,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T00:00:00Z","timestamp":1644537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016935","name":"Lisa Dean Moseley Foundation","doi-asserted-by":"publisher","award":["unnumbered"],"award-info":[{"award-number":["unnumbered"]}],"id":[{"id":"10.13039\/100016935","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Leukemia Research Foundation of Delaware","award":["unnumbered"],"award-info":[{"award-number":["unnumbered"]}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM103446"],"award-info":[{"award-number":["P20GM103446"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P30GM114736"],"award-info":[{"award-number":["P30GM114736"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016610","name":"Andrew McDonough B+ Foundation","doi-asserted-by":"publisher","award":["unnumbered"],"award-info":[{"award-number":["unnumbered"]}],"id":[{"id":"10.13039\/100016610","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012465","name":"Nemours Foundation","doi-asserted-by":"publisher","award":["unnumbered"],"award-info":[{"award-number":["unnumbered"]}],"id":[{"id":"10.13039\/100012465","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Energy","award":["DE-AC52-07NA27344"],"award-info":[{"award-number":["DE-AC52-07NA27344"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Children with Down syndrome (DS) have a high risk for acute myeloid leukemia (DS-ML). Genomic characterization of DS-ML blasts showed the presence of unique mutations in GATA1, an essential hematopoietic transcription factor, leading to the production of a truncated from of GATA1 (GATA1s). GATA1s, together with trisomy 21, is sufficient to develop a pre-leukemic condition called transient abnormal myelopoiesis (TAM). Approximately 30% of these cases progress into DS-ML by acquisition of additional somatic mutations in a stepwise manner. We previously developed a model for TAM by introducing disease-specific GATA1 mutation in trisomy 21-induced pluripotent stem cells (iPSCs), leading to the production of N-terminally truncated short form of GATA1 (GATA1s). In this model, we used CRISPR\/Cas9 to introduce a co-operating mutation in STAG2, a member of the cohesin complex recurrently mutated in DS-ML but not in TAM. Hematopoietic differentiation of GATA1\u00a0STAG2 double-mutant iPSC lines confirmed GATA1s expression and the loss of functional STAG2 protein, leading to enhanced production of immature megakaryocytic population compared to GATA1 mutant alone. Megakaryocyte-specific lineage expansion of the double-mutant HSPCs exhibited close resemblance to the DS-ML immunophenotype. Transcriptome analysis showed that GATA1 mutation resulted in downregulation of megakaryocytic and erythrocytic differentiation pathways and interferon \u03b1\/\u03b2 signaling, along with an upregulation of pathways promoting myeloid differentiation such as toll-like receptor cascade. The co-occurrence of STAG2 knockout partially reverted the expression of genes involved in myeloid differentiation, likely leading to enhanced self-renewal and promoting leukemogenesis. In conclusion, we developed a DS-ML model via hematopoietic differentiation of gene-targeted iPSCs bearing trisomy 21.<\/jats:p>","DOI":"10.3390\/cells11040628","type":"journal-article","created":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T20:32:30Z","timestamp":1644784350000},"page":"628","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4162-3004","authenticated-orcid":false,"given":"Sonali P.","family":"Barwe","sequence":"first","affiliation":[{"name":"Nemours Centers for Childhood Cancer Research & Cancer and Blood Disorders, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"},{"name":"Department of Biological Sciences, University of Delaware, Newark, DE 19711, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7822-7040","authenticated-orcid":false,"given":"Aimy","family":"Sebastian","sequence":"additional","affiliation":[{"name":"Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ishnoor","family":"Sidhu","sequence":"additional","affiliation":[{"name":"Nemours Centers for Childhood Cancer Research & Cancer and Blood Disorders, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"},{"name":"Department of Biological Sciences, University of Delaware, Newark, DE 19711, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward Anders","family":"Kolb","sequence":"additional","affiliation":[{"name":"Nemours Centers for Childhood Cancer Research & Cancer and Blood Disorders, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0465-578X","authenticated-orcid":false,"given":"Anilkumar","family":"Gopalakrishnapillai","sequence":"additional","affiliation":[{"name":"Nemours Centers for Childhood Cancer Research & Cancer and Blood Disorders, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"},{"name":"Department of Biological Sciences, University of Delaware, Newark, DE 19711, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.3324\/haematol.2010.024968","article-title":"Acute leukemia in children with Down syndrome","volume":"95","author":"Xavier","year":"2010","journal-title":"Haematologica"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s12185-016-1959-5","article-title":"Evolution of myeloid leukemia in children with Down syndrome","volume":"103","author":"Saida","year":"2016","journal-title":"Int. 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