Early Lineage Priming by Trisomy of Erg Leads to Myeloproliferation in a Down Syndrome Model

Abstract

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 GATA1 mutations, transient myeloproliferative disorder (DS-TMD) and acute megakaryocytic leukemia (DS-AMKL). Trisomy of the Erg gene is required for myeloproliferation in the Ts(1716)65Dn DS mouse model. We demonstrate here that genetic changes specifically attributable to trisomy of Erg 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 Erg 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 ERG as a regulator of hematopoietic lineage potential, and that trisomy of ERG in the context of DS foetal liver hemopoiesis drives the pre-leukemic changes that predispose to subsequent DS-TMD and DS-AMKL.

An Erg driven transcriptional program controls B-lymphopoiesis

“…Erg expression in adult hematopoiesis was first examined by generating mice carrying the Erg tm1a(KOMP)wtsi knock-in first reporter allele (Erg KI ) (Figure 1A). Consistent with the known role for Erg in hematopoiesis 17,18,19,20,21 , significant LacZ expression driven by the endogenous Erg promoter was observed in hematopoietic stem cells (HSCs) and multipotential progenitor cells, as well as in granulocyte-macrophage and megakaryocyte-erythroid progenitor populations, with declining activity accompanying erythroid maturation (Figure 1B with definitions of cells examined provided in Table S1 and representative flow cytometry plots in Figure S1). In other lineages, transcription from the Erg locus was evident in common lymphoid (CLP), all lymphoid (ALP) and B-cell-biased lymphoid (BLP) progenitor cells, as well as in B-lineage committed pre-proB, proB and preB cells and double-negative thymic Tlymphoid cell subsets, with a reduction in transcription with later B-cell and T-cell maturation (Figure 1B,C).…”

“…To build on prior work defining the role of the hematopoietic transcription factor Erg in regulation of haematopoietic stem cells (HSCs) 17 and megakaryocyte-erythroid specification 18 , we sought to identify whether Erg played roles in other haemopoietic lineages. Erg expression in adult hematopoiesis was first examined by generating mice carrying the Erg tm1a(KOMP)wtsi knock-in first reporter allele (Erg KI ) (Figure 1A).…”

Altered B-lymphopoiesis in mice with deregulated thrombopoietin signaling

“…Gene set tests were performed using gene sets obtained for the CLP, ProB and PreB populations from the Hemopedia atlas (haemosphere.org) 18 using the top 77 upregulated genes for each population compared to the highest gene expression across the entire dataset. Using the Roast function in Limma, a self-contained rotational gene set testing method 37 , gene set enrichment was tested in Mpl −/− and Tpo Tg LSKs when compared to wild-type and leading-edge genes contributing to the enriched CLP expression signature in Mpl −/− LSK cells, as well as downregulated CLP expression signature in Tpo Tg LSK cells, were extracted (Supplementary Table S1 ).…”

Rodent models in Down syndrome research: impact and future opportunities

“…This summary is not exhaustive and many additional DS features have been explored using mouse models, such as the mineralisation of long bones ( Blazek et al, 2015 ), the risk of chronic otitis media ( Bhutta et al, 2013 ), and the higher risk of developing myeloproliferative disorders and cancer ( Ng et al, 2015 ; Sussan et al, 2008 ; Malinge et al, 2012 ; Alford et al, 2010 ; Yang et al, 2016 ). Each mouse strain has the potential to provide unique information, and a range of animals, aneuploid and partially trisomic, are important to pinpoint specific candidate genes and dissect the underlying molecular mechanisms.…”