Epigenetic remodeling underlies the development of Down syndrome-related acute megakaryoblastic leukemia

Children with Down syndrome (DS) have an elevated risk of myeloid leukemia in DS (ML-DS). In addition to a truncated form of GATA1 (GATA1s), ML-DS requires other somatic gene mutations, among which cohesin and polycomb repressive complex 2 (PRC2) gene mutations are most frequently identified. Here, we show that GATA1s and cohesin and/or PRC2 insufficiencies cooperate in the development of ML-DS. Transplantation of GATA1s fetal liver cells followed by deletion of STAG2, a cohesin gene, and/or EZH, a PRC2 gene, promoted biased differentiation towards megakaryocytic lineage and enhanced megakaryocyte progenitor expansion, accompanied by lethal myelofibrosis. Mechanistically, loss of STAG2 or EZH2 reinforced GATA1s-driven reduced chromatin accessibility of erythroid transcription factors in megakaryocyte/erythroid progenitors, thereby allowing biased differentiation towards megakaryocytic lineage. Loss of STAG2 or EZH2 also counteracted GATA1s-driven globally elevated H3K27me3 levels to induce a PRC2 insufficient state, resulting in derepression of a substantial portion of PRC2 target genes in megakaryocyte/erythroid progenitors. Notably, chromosome 21-encoded miR-125b efficiently blocked megakaryocytic differentiation of GATA1s progenitors in the absence of STAG2 or EZH2, and transformed them only upon concurrent loss of STAG2 and EZH2, promoting expansion of CD150+Sca-1+c-Kit+ leukemic stem cell-like cells that induced AMKL in mice. Our findings indicate that cohesin and PRC2 insufficiencies have both overlapping and distinct epigenetic effects in the development of ML-DS, thereby acting synergistically in the epigenetic remodeling of trisomy 21/GATA1s preleukemic state for full transformation.