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Polycomb repressive complex 2 insufficiency underlies myeloid leukemia in Down syndrome

Yutaro Suzuki1, Yaeko Nakajima-Takagi1, Motohiko Oshima1

  • 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.

Blood
|April 8, 2026
PubMed

Insights

Children with Down syndrome (DS) face higher risks of myeloid leukemia (ML-DS). This study reveals that cohesin and polycomb repressive complex 2 (PRC2) gene insufficiencies, combined with GATA1 mutations, drive ML-DS by altering epigenetic landscapes and promoting leukemic cell growth.

Area of Science:

  • Hematology
  • Epigenetics
  • Cancer Biology

Background:

  • Children with Down syndrome (DS) have an increased risk of myeloid leukemia in DS (ML-DS).
  • ML-DS development involves GATA1 mutations (producing GATA1-short) and additional somatic mutations, frequently in cohesin and polycomb repressive complex 2 (PRC2) genes.
  • The precise roles of cohesin and PRC2 in ML-DS pathogenesis remain incompletely understood.

Purpose of the Study:

  • To investigate the role of PRC2 insufficiency in ML-DS pathogenesis.
  • To elucidate the mechanistic interplay between GATA1s, cohesin loss (Stag2), and PRC2 loss (Ezh2) in driving leukemogenesis.
  • To understand how these genetic alterations synergize with trisomy 21 to remodel the epigenetic landscape.

Main Methods:

  • Transplantation of Gata1s fetal liver cells in a mouse model.
  • Genetic deletion of cohesin subunit Stag2 and/or PRC2 component Ezh2.
  • Analysis of megakaryocyte differentiation, progenitor expansion, chromatin accessibility, and gene expression (H3K27me3 levels).
  • Investigating the role of miR-125b in leukemic transformation.

Main Results:

  • Loss of Stag2 or Ezh2 in Gata1s progenitors reduced chromatin accessibility at erythroid loci, promoting megakaryocytic skewing.
  • Ezh2 loss led to global H3K27me3 reduction and derepression of PRC2 target genes, creating a PRC2-insufficient state.
  • Stag2 loss also induced a PRC2-insufficient state in Gata1s progenitors.
  • Concurrent loss of Stag2 and Ezh2, along with miR-125b, drove full transformation and expansion of leukemic stem cell-like populations, resulting in acute megakaryoblastic leukemia.

Conclusions:

  • PRC2 insufficiency is a key driver of ML-DS pathogenesis.
  • Cohesin and PRC2 insufficiencies converge on PRC2 dysfunction but exert distinct epigenetic effects.
  • These genetic alterations synergize with trisomy 21 and GATA1s to drive leukemia progression from a preleukemic state to overt disease.

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