Early lineage priming by trisomy of Erg leads to myeloproliferation in a down syndrome model

Ashley Quan Ping Ng; Yifang Hu; Donald Metcalf; Craig D Hyland; Helen Ierino; Belinda Phipson; Di Wu; Tracey M Baldwin; Maria Kauppi; Hiu Kiu; Ladina Di Rago; Douglas James Hilton; Gordon K Smyth; Warren S Alexander

doi:10.1371/journal.pgen.1005211

Early lineage priming by trisomy of Erg leads to myeloproliferation in a down syndrome model

Ashley Quan Ping Ng, Yifang Hu, Donald Metcalf, Craig D Hyland, Helen Ierino, Belinda Phipson, Di Wu, Tracey M Baldwin, Maria Kauppi, Hiu Kiu, Ladina Di Rago, Douglas James Hilton, Gordon K Smyth, Warren S Alexander

Hudson Institute - Centre for Cancer Research

Research output: Contribution to journal › Article › Research › peer-review

8 Citations (Scopus)

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.

Original language	English
Article number	e1005211
Number of pages	19
Journal	PLoS Genetics
Volume	11
Issue number	5
DOIs	https://doi.org/10.1371/journal.pgen.1005211
Publication status	Published - 2015

Access to Document

10.1371/journal.pgen.1005211Licence: CC BY

3508115-oaFinal published version, 892 KBLicence: CC BY

RM sElocation

Cite this

Ng, A. Q. P., Hu, Y., Metcalf, D., Hyland, C. D., Ierino, H., Phipson, B., Wu, D., Baldwin, T. M., Kauppi, M., Kiu, H., Di Rago, L., Hilton, D. J., Smyth, G. K., & Alexander, W. S. (2015). Early lineage priming by trisomy of Erg leads to myeloproliferation in a down syndrome model. PLoS Genetics, 11(5), [e1005211]. https://doi.org/10.1371/journal.pgen.1005211

Ng, Ashley Quan Ping ; Hu, Yifang ; Metcalf, Donald ; Hyland, Craig D ; Ierino, Helen ; Phipson, Belinda ; Wu, Di ; Baldwin, Tracey M ; Kauppi, Maria ; Kiu, Hiu ; Di Rago, Ladina ; Hilton, Douglas James ; Smyth, Gordon K ; Alexander, Warren S. / Early lineage priming by trisomy of Erg leads to myeloproliferation in a down syndrome model. In: PLoS Genetics. 2015 ; Vol. 11, No. 5.

@article{f8fb121c5e5642e0b4c8c7edcc2a1ae0,

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.",

author = "Ng, {Ashley Quan Ping} and Yifang Hu and Donald Metcalf and Hyland, {Craig D} and Helen Ierino and Belinda Phipson and Di Wu and Baldwin, {Tracey M} and Maria Kauppi and Hiu Kiu and {Di Rago}, Ladina and Hilton, {Douglas James} and Smyth, {Gordon K} and Alexander, {Warren S}",

year = "2015",

doi = "10.1371/journal.pgen.1005211",

language = "English",

volume = "11",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "5",

}

Early lineage priming by trisomy of Erg leads to myeloproliferation in a down syndrome model. / Ng, Ashley Quan Ping; Hu, Yifang; Metcalf, Donald; Hyland, Craig D; Ierino, Helen; Phipson, Belinda; Wu, Di; Baldwin, Tracey M; Kauppi, Maria; Kiu, Hiu; Di Rago, Ladina; Hilton, Douglas James; Smyth, Gordon K; Alexander, Warren S.

In: PLoS Genetics, Vol. 11, No. 5, e1005211, 2015.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Early lineage priming by trisomy of Erg leads to myeloproliferation in a down syndrome model

AU - Ng, Ashley Quan Ping

AU - Hu, Yifang

AU - Metcalf, Donald

AU - Hyland, Craig D

AU - Ierino, Helen

AU - Phipson, Belinda

AU - Wu, Di

AU - Baldwin, Tracey M

AU - Kauppi, Maria

AU - Kiu, Hiu

AU - Di Rago, Ladina

AU - Hilton, Douglas James

AU - Smyth, Gordon K

AU - Alexander, Warren S

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431731/pdf/pgen.1005211.pdf

U2 - 10.1371/journal.pgen.1005211

DO - 10.1371/journal.pgen.1005211

M3 - Article

VL - 11

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 5

M1 - e1005211

ER -