Early Lineage Priming by Trisomy of <i>Erg</i> Leads to Myeloproliferation in a Down Syndrome Model

<div><p>Down syndrome (DS), with trisomy of chromosome 21 (HSA21), is the commonest human aneuploidy. Pre-leukemic myeloproliferative changes in DS foetal livers precede the acquisition of <i>GATA1</i> mutations, transient myeloproliferative disorder (DS-TMD) and acute megakaryocytic leukemia (DS-AMKL). Trisomy of the <i>Erg</i> gene is required for myeloproliferation in the Ts(17¹⁶)65Dn DS mouse model. We demonstrate here that genetic changes specifically attributable to trisomy of <i>Erg</i> lead to lineage priming of primitive and early multipotential progenitor cells in Ts(17¹⁶)65Dn mice, excess megakaryocyte-erythroid progenitors, and malignant myeloproliferation. Gene expression changes dependent on trisomy of <i>Erg</i> in Ts(17¹⁶)65Dn multilineage progenitor cells were correlated with those associated with trisomy of HSA21 in human DS hematopoietic stem and primitive progenitor cells. These data suggest a role for <i>ERG</i> as a regulator of hematopoietic lineage potential, and that trisomy of <i>ERG</i> in the context of DS foetal liver hemopoiesis drives the pre-leukemic changes that predispose to subsequent DS-TMD and DS-AMKL.</p>