title: 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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ashley P
authors.initials: AP
authors.lastname: Ng
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Craig D
authors.initials: CD
authors.lastname: Hyland
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Ierino
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Belinda
authors.initials: B
authors.lastname: Phipson
authors.affiliation: Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia; Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Tracey M
authors.initials: TM
authors.lastname: Baldwin
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Kauppi
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Hiu
authors.initials: H
authors.lastname: Kiu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Ladina
authors.initials: L
authors.lastname: Di Rago
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000483:Alleles; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D019070:Cell Lineage; D049109:Cell Proliferation; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics*; D041905:Erythroid Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D006410:Hematopoiesis / Q000235:genetics; D006413:Hematopoietic System / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D015513:Oncogene Proteins / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000071230:Transcriptional Regulator ERG; D059467:Transcriptome; D014314:Trisomy
chemical_list: D018952:Antigens, CD34; C072312:ERG protein, human; C531115:ERG protein, mouse; D015513:Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D051997:ADP-ribosyl Cyclase 1