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.
Highlights
Down syndrome (DS) is the commonest human aneuploidy [1]
An excess number of genes in trisomy on human chromosome 21 leads to the development of specific diseases in human Down syndrome
In this study we show how trisomy of Erg in a murine Down syndrome model perturbs hematopoietic progenitor cells in a manner similar to that observed in human Down syndrome by inducing gene expression changes and lineage priming in early multi-potential progenitors
Summary
Down syndrome (DS) is the commonest human aneuploidy [1]. DS infants with trisomy of human chromosome 21 (HSA21) are uniquely predisposed to a transient myeloproliferative disorder (DS-TMD) and acute megakaryocytic leukemia (DS-AMKL) [2]. Increased numbers and clonogenicity of hematopoietic stem (HSC) and progenitor cells, increased frequency of bi-potential megakaryocyte-erythroid progenitors, and reduced numbers of granulocyte-macrophage-committed progenitor cells have been described [13,14,15]. This perturbation must be attributed to a specific trisomic gene or genes on HSA21 that drive the pre-leukemic DS phenotype from which DS-AMKL and DS-TMD subsequently arise. Blasts with erythro-megakaryocytic features and myelofibrosis are commonly observed in organs affected by DS-TMD/AMKL, while DS foetal livers show increased numbers of bipotential megakaryocyte-erythroid progenitors with increased clonogenicity and megakaryocyte/erythroid potential as well as megakaryocytosis [13,14,15]
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