ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification

Taoudi, Samir; Bee, Thomas; Hilton, Adrienne; Knezevic, Kathy; Scott, Julie A.; Willson, Tracy A.; Collin, Caitlin; Thomas, Tim; Voss, Anne K.; Kile, Benjamin T.; Alexander, Warren S.; Pimanda, John E.; Hilton, Douglas J.

doi:10.1101/gad.2009211

Cited by 109 publications

(113 citation statements)

References 58 publications

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“…ERG was recently demonstrated to be required for maintenance of the FL HSCs. 23 We show here for the first time that constitutive hematopoietic expression of human ERG causes expansion of FL MEPs in a mouse model with no other genetic aberrations related to DS. Although Gata1s enhanced early fetal megakaryopoiesis, as previously reported, 11 it did not affect the percentage of MEPs.…”

Section: Discussionmentioning

confidence: 98%

“…GATA2 expression is directly activated by ERG and repressed by GATA1. 23,39 In G1ME cells, 30 Gata2 expression was reduced by an average of threefold upon expression of Gata1 compared with Gata1s-expressing G1ME cells ( Figure 6D-E). In E14.5 Wt/Gata1s FL cells transduced with GATA1, GATA2 expression was reduced by an average of 1.7-fold compared with its expression in E14.5 FL cells that expressed only GATA1s ( Figure 6F).…”

Section: /Cd71mentioning

confidence: 98%

“…6 ERG is essential for maintenance of fetal hematopoietic stem cells (HSCs). 21,23 It is one of a heptad of transcription factors, bound in combinatorial interactions to HSC enhancers. 24 Developmental cooperation between ERG and GATA1 has been suggested by demonstrating their cobinding to regulatory elements of key hematopoietic genes such as Scl/Tal1.…”

Section: Introductionmentioning

confidence: 99%

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

Birger

Goldberg

Chlon

et al. 2013

Blood

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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)

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Section: Discussionmentioning

confidence: 98%

Section: /Cd71mentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Birger

Goldberg

Chlon

et al. 2013

Blood

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“…Based on the data we have presented, we can now propose a similar role for TMPRSS2/ ERG in the early stages of human PCa. As shown in haematopoietic CSCs 23,24 and more recently in a prostate transgenic mouse model 25 , ERG expression can indeed influence self-renewal and maintenance of the stem cell pool. As the SC are likely to have a longer life span (together with their immediate progeny the TA cells) they have been proposed as the cells most likely to accumulate the necessary genetic (and epigenetic) changes required to escape niche dependence and normal growth/survival controls.…”

Section: Discussionmentioning

confidence: 99%

Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells

et al. 2013

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While chromosomal translocations have a fundamental role in the development of several human leukaemias, their role in solid tumour development has been somewhat more controversial. Recently, it was shown that up to 80% of prostate tumours harbour at least one such gene fusion, and that the most common fusion event, between the prostate-specific TMPRSS2 gene and the ERG oncogene, is a critical, and probably early factor in prostate cancer development. Here we demonstrate the presence and expression of this significant chromosomal rearrangement in prostate cancer stem cells. Moreover, we show that in the prostate epithelial hierarchy from both normal and tumour tissues, TMPRSS2 transcription is subjected to tight monoallelic regulation, which is retained upon asymmetric division and relaxed during epithelial cell differentiation. The presence and expression of TMPRSS2/ERG in prostate stem cells would provide ERG-driven survival advantages, allowing maintenance of this mutated genotype.

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“…ETS proteins are a family of over 20 helix-loop-helix domain transcription factors with diverse biological roles, including important functions in hematopoiesis and leukemia. In normal hematopoiesis, Erg is required for hematopoietic stem cell self-renewal during times of high hematopoietic stem cell cycling (11)(12)(13). 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).…”

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.

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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 ...

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ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification

Cited by 109 publications

References 58 publications

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

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

Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells

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

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