Polycomb repressive complex 2 insufficiency underlies myeloid leukemia in Down syndrome

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.