Polycomb repressive complex 2 insufficiency underlies myeloid leukemia in Down syndrome

作者：Yutaro Suzuki, Yaeko Nakajima-Takagi, Motohiko Oshima, Yotaro Ochi, Akiho Tsuchiya, Shuhei Koide, Takako Yokomizo‐Nakano, Shuhei Kurosawa, Ola Rizq, Ayana Kon, S. Miyano, Bahityar Rahmutulla, Atsushi Kaneda, Manabu Nakayama, H. Koseki, Eugene Yu, Tsutomu Toki, Etsuro Ito, Seishi Ogawa, Atsushi Iwama · 发表于：Blood · 年份：2026 · DOI：10.1182/blood.2025032083 · 被引用次数：1 · 研究领域：Acute Myeloid Leukemia Research、Acute Lymphoblastic Leukemia research、Hemoglobinopathies and Related Disorders

ABSTRACT: 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-encoded 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-like populations only upon concurrent loss of ...