Polycomb repressive complex 2 insufficiency underlies myeloid leukemia in Down syndrome - PubMed
6 hours ago
- #PRC2 insufficiency
- #GATA1s mutations
- #Down syndrome leukemia
- Children with Down syndrome (DS) have a higher risk of developing myeloid leukemia in DS (ML-DS).
- ML-DS requires mutations in GATA1, generating GATA1s, and additional mutations often in cohesin and PRC2 genes.
- PRC2 insufficiency drives ML-DS pathogenesis, shown by transplanting Gata1s cells and deleting Stag2 or Ezh2.
- Loss of Stag2 or Ezh2 reinforces Gata1s-driven reduced chromatin accessibility, promoting megakaryocytic skewing.
- Ezh2 loss attenuates Gata1s-mediated H3K27me3 elevation, derepressing PRC2 target genes, creating PRC2-insufficient state.
- Stag2 loss also induces a moderate PRC2-insufficient state in Gata1s progenitors.
- miR-125b from chromosome 21 blocks megakaryocytic differentiation with single gene loss but drives full transformation with both Stag2 and Ezh2 loss.
- Cohesin and PRC2 insufficiencies converge on PRC2 dysfunction, synergizing with trisomy 21 and GATA1s to progress from preleukemic to overt leukemia.