{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:24:14Z","timestamp":1790267054333,"version":"4.1.0"},"reference-count":52,"publisher":"American Society of Hematology","issue":"4","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,7,23]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Children with Down syndrome (DS) have an elevated risk of developing myeloid leukemia (ML; ML in DS [ML-DS]). In addition to mutations in GATA1, which generate the truncated isoform GATA1-short (GATA1s), ML-DS requires additional somatic gene mutations, most frequently in cohesion and Polycomb repressive complex 2 (PRC2) genes. Here, we show that PRC2 insufficiency underlies ML-DS pathogenesis. Transplantation of Gata1s fetal liver cells followed by deletion of the cohesion subunit Stag2 and\/or the PRC2 component Ezh2 induced megakaryocyte-biased differentiation and expansion of megakaryocytic progenitors, culminating in lethal myelofibrosis. Mechanistically, loss of Stag2 or Ezh2 reinforced Gata1s-driven reduced chromatin accessibility at erythroid transcription factor target loci in premegakaryocyte\/erythroid progenitors (pre-MegEs), thereby promoting megakaryocytic skewing. Ezh2 loss attenuated the Gata1s-mediated global elevation of H3K27 trimethylation in pre-MegEs, resulting in derepression of a broad set of PRC2 target genes and establishing a functionally PRC2-insufficient state. Similarly, Stag2 loss induced a moderate but significant degree of PRC2-insufficient state in Gata1s progenitors. Furthermore, chromosome 21\u2013encoded miR-125b blocked megakaryocytic differentiation of Gata1s progenitors lacking either Stag2 or Ezh2 alone but drove full transformation and expansion of CD150+Sca-1+c-Kit+ leukemic stem cell\u2013like populations only upon concurrent loss of both Stag2 and Ezh2, leading to acute megakaryoblastic leukemia in mice. These findings reveal that cohesin and PRC2 insufficiencies converge on PRC2 dysfunction while exerting distinct epigenetic effects and synergize with trisomy 21 and GATA1s to remodel the epigenetic landscape, driving progression from a preleukemic state to overt leukemia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025032083","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T16:24:39Z","timestamp":1775665479000},"page":"462-476","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":2,"title":["Polycomb repressive complex 2 insufficiency underlies myeloid leukemia in Down syndrome"],"prefix":"10.1182","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6621-2482","authenticated-orcid":false,"given":"Yutaro","family":"Suzuki","sequence":"first","affiliation":[{"name":"1Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaeko","family":"Nakajima-Takagi","sequence":"additional","affiliation":[{"name":"1Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motohiko","family":"Oshima","sequence":"additional","affiliation":[{"name":"1Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yotaro","family":"Ochi","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, 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