Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome

Ng, Ashley P; Hyland, Craig D.; Metcalf, Donald; Carmichael, Catherine; Loughran, Stephen J.; Rago, Ladina Di; Kile, Benjamin T.; Alexander, Warren S.

doi:10.1182/blood-2009-09-242107

Cited by 69 publications

(70 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although ERG autoinhibition has been biochemically characterized in a recent study (29), our current report presents structures of ERG and characterization of the molecular mechanism of autoinhibition. The changes in ERG activity we identified here, ∼fivefold weaker binding in ERGi and threefold weaker binding in full-length ERG, are highly relevant in a biological context, because a change in ERG expression of as little as 50% is sufficient to alter angiogenesis (13), myeloproliferation (8), and maintenance of the hematopoietic stem cell population (7,12).…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of the ERG gene product, located on chromosome 21, has also been implicated in the myeloproliferative disorders frequently seen in Down Syndrome patients (8), has been shown to have a dedifferentiating effect (9), and confers greater invasiveness to cell lines (10,11). Importantly, the aberrant expression or deletion/loss of function of a single copy of the ERG allele can produce profound phenotypes (8,12,13), indicating that a change in ERG activity of as little as twofold compared with wild type can have a tremendous impact.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Structural and dynamic studies of the transcription factor ERG reveal DNA binding is allosterically autoinhibited

Regan

Horanyi

Pryor

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

123

View full text Add to dashboard Cite

The Ets-Related Gene (ERG) belongs to the Ets family of transcription factors and is critically important for maintenance of the hematopoietic stem cell population. A chromosomal translocation observed in the majority of human prostate cancers leads to the aberrant overexpression of ERG. We have identified regions flanking the ERG Ets domain responsible for autoinhibition of DNA binding and solved crystal structures of uninhibited, autoinhibited, and DNA-bound ERG. NMR-based measurements of backbone dynamics show that uninhibited ERG undergoes substantial dynamics on the millisecond-to-microsecond timescale but autoinhibited and DNA-bound ERG do not. We propose a mechanism whereby the allosteric basis of ERG autoinhibition is mediated predominantly by the regulation of Ets-domain dynamics with only modest structural changes.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Structural and dynamic studies of the transcription factor ERG reveal DNA binding is allosterically autoinhibited

Regan

Horanyi

Pryor

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

123

View full text Add to dashboard Cite

show abstract

“…Whereas the ERG locus has been studied extensively in prostate cancer, in which translocation of ERG to the TMPRSS2 locus and expression of a TMPRSS2-ERG fusion oncoprotein occurs in the majority of cases (8), ERG is also known to be translocated to the fused in sarcoma/translocated in liposarcoma (FUS/TLS) locus in rare cases of acute myeloid leukemia (AML). Moreover, increased expression of ERG is associated with poor prognosis in cytogenetically normal AML and T cell acute lymphoblastic leukemia (T-ALL) (7), and the ERG gene resides in the critical region of chromosome 21 that is associated with myeloproliferation and leukemia in Down syndrome (14,15). Ets-1 is also important for normal hematopoiesis, being involved in the development of both lymphoid and myeloid cell lineages (16).…”

Section: Discussionmentioning

confidence: 99%

Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia

Tang

Carmichael

Shi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

To define genetic lesions driving leukemia, we targeted credependent Sleeping Beauty (SB) transposon mutagenesis to the blood-forming system using a hematopoietic-selective vav 1 oncogene (vav1) promoter. Leukemias of diverse lineages ensued, most commonly lymphoid leukemia and erythroleukemia. The inclusion of a transgenic allele of Janus kinase 2 (JAK2)V617F resulted in acceleration of transposon-driven disease and strong selection for erythroleukemic pathology with transformation of bipotential erythro-megakaryocytic cells. The genes encoding the E-twenty-six (ETS) transcription factors Ets related gene (Erg) and Ets1 were the most common sites for transposon insertion in SB-induced JAK2V617F-positive erythroleukemias, present in 87.5% and 65%, respectively, of independent leukemias examined. The role of activated Erg was validated by reproducing erythroleukemic pathology in mice transplanted with fetal liver cells expressing translocated in liposarcoma (TLS)-ERG, an activated form of ERG found in human leukemia. Via application of SB mutagenesis to TLS-ERG-induced erythroid transformation, we identified multiple loci as likely collaborators with activation of Erg. Jak2 was identified as a common transposon insertion site in TLS-ERG-induced disease, strongly validating the cooperation between JAK2V617F and transposon insertion at the Erg locus in the JAK2V617F-positive leukemias. Moreover, loci expressing other regulators of signal transduction pathways were conspicuous among the common transposon insertion sites in TLS-ERGdriven leukemia, suggesting that a key mechanism in erythroleukemia may be the collaboration of lesions disturbing erythroid maturation, most notably in genes of the ETS family, with mutations that reduce dependence on exogenous signals.T he study of cancer-causing genes using insertional mutagenesis in the mouse (1, 2) provides a powerful complement to human cancer genomics for functional identification and characterization of the genetic lesions driving tumor development. Transposons are DNA elements with the unique capacity to change their genomic position, usually via expression of a transposase, an enzyme that catalyzes excision of the transposon from the genome and facilitates its reintegration elsewhere. Although most mammals lack active endogenous transposons, the Sleeping Beauty (SB) system has been developed recently to adapt the well-studied fish Tc/mariner transposon to allow insertional mutagenesis in the mouse (2). Temporally controlled or tissue-specific SB-mediated genetic screens have been designed by imposing cre-recombinase control over the expression of the transposase (2). Moreover, by activating transposition in mice carrying a predisposing germ-line genetic lesion, insertional mutations that cooperate with that particular lesion in cancer pathogenesis can be isolated specifically.To define genetic lesions driving leukemia, we targeted SB transposon mutagenesis to the blood-forming system by intercrossing mice transgenic for both a transposon array and a cre-inducible ...

show abstract

“…6,16,17 Further support to the hematopoietic role of ERG was recently given by an experiment in which reversing ERG trisomy to functional disomy in the Ts65Dn mouse model of DS corrected the myeloproliferative syndrome observed in these adult mice. 27 Yet, unlike human DS fetuses, no prenatal hematopoietic abnormalities were reported in Ts65Dn mice.…”

Section: Introductionmentioning

confidence: 99%

Perturbation of fetal hematopoiesis in a mouse model of Down syndrome’s transient myeloproliferative disorder

Birger

Goldberg

Chlon

et al. 2013

Blood

View full text Add to dashboard Cite

Key Points• Transient expansion of fetal megaerythroid progenitors in ERG/Gata1s mouse is biologically similar to Down syndrome TMD.• The N-terminal domain of GATA1 and the downregulation of ERG expression are essential for normal fetal erythropoiesis.Children with Down syndrome develop a unique congenital clonal megakaryocytic proliferation disorder (transient myeloproliferative disorder [TMD]). It is caused by an expansion of fetal megakaryocyte-erythroid progenitors (MEPs) triggered by trisomy of chromosome 21 and is further enhanced by the somatic acquisition of a mutation in GATA1. These mutations result in the expression of a short-isoform GATA1s lacking the N-terminal domain. To examine the hypothesis that the Hsa21 ETS transcription factor ERG cooperates with GATA1s in this process, we generated double-transgenic mice expressing hERG and Gata1s. We show that increased expression of ERG by itself is sufficient to induce expansion of MEPs in fetal livers. Gata1s expression synergizes with ERG in enhancing the expansion of fetal MEPs and megakaryocytic precursors, resulting in hepatic fibrosis, transient postnatal thrombocytosis, anemia, a gene expression profile that is similar to that of human TMD and progression to progenitor myeloid leukemia by 3 months of age. This ERG/Gata1s transgenic mouse model also uncovers an essential role for the N terminus of Gata1 in erythropoiesis and the antagonistic role of ERG in fetal erythroid differentiation and survival. The human relevance of this finding is underscored by the recent discovery of similar mutations in GATA1 in patients with Diamond-Blackfan anemia. (Blood. 2013;122(6):988-998)

show abstract

Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome

Cited by 69 publications

References 18 publications

Structural and dynamic studies of the transcription factor ERG reveal DNA binding is allosterically autoinhibited

Structural and dynamic studies of the transcription factor ERG reveal DNA binding is allosterically autoinhibited

Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia

Perturbation of fetal hematopoiesis in a mouse model of Down syndrome’s transient myeloproliferative disorder

Contact Info

Product

Resources

About