The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells

“…A more modest reduction in megakaryocyte progenitor cells was evident in the tissues of Erg ϩ/ Mld2 mice, as described in ref. 12. In Fli-1 ϩ/Ϫ mice, the numbers of these cells was normal ( Fig.…”

Section: A Genetic Interaction Between Fli-1 and Ergmentioning

confidence: 99%

“…Analyses of Erg ϩ/Mld2 adult mice revealed that Erg is required for normal adult HSC homeostasis. HSCs are reduced in number in Erg ϩ/Mld2 mice and unable to compete effectively with Erg ϩ/ϩ cells to reconstitute irradiated transplant recipients (12).…”

mentioning

confidence: 99%

Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage

Kruse

Loughran

Baldwin³

et al. 2009

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

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Fli-1 and Erg are closely related members of the Ets family of transcription factors. Both genes are translocated in human cancers, including Ewing's sarcoma, leukemia, and in the case of Erg, more than half of all prostate cancers. Although evidence from mice and humans suggests that Fli-1 is required for megakaryopoiesis, and that Erg is required for normal adult hematopoietic stem cell (HSC) regulation, their precise physiological roles remain to be defined. To elucidate the relationship between Fli-1 and Erg in hematopoiesis, we conducted an analysis of mice carrying mutations in both genes. Our results demonstrate that there is a profound genetic interaction between Fli-1 and Erg. Double heterozygotes displayed phenotypes more dramatic than single heterozygotes: severe thrombocytopenia, with a significant deficit in megakaryocyte numbers and evidence of megakaryocyte dysmorphogenesis, and loss of HSCs accompanied by a reduction in the number of committed hematopoietic progenitor cells. These results illustrate an indispensable requirement for both Fli-1 and Erg in normal HSC and megakaryocyte homeostasis, and suggest these transcription factors may coregulate common target genes.T he E-twenty-six specific (Ets) proteins are a family of more than 20 helix-loop-helix domain transcription factors that have been implicated in a myriad of cellular processes (1). Fli-1 and Erg are Ets proteins that share greater homology to each other than to other Ets family members. Fli-1 is mutated in a number of cancers, including Ewing's sarcoma and erythroleukemia (2, 3). Genetic manipulation in mice (4, 5) and mutations in humans (4, 6) have revealed multiple roles for Fli-1 in hematopoiesis including the production of megakaryocytes and platelets. Fli-1 is also implicated in the regulation of important stem cell genes, suggesting a role within the hematopoietic stem cell compartment (7,8). Erg is also a proto-oncogene, translocated in Ewing sarcoma, leukemia, and prostate cancer (9-11). We recently reported a mouse model of Erg dysfunction, Erg Mld2 , in which an N-ethyl-N-nitrosourea (ENU)-induced point mutation causes profound loss of Erg function. These mice revealed an indispensable requirement for Erg in definitive hematopoiesis with Erg Mld2/Mld2 embryos dying at midgestation. Analyses of Erg ϩ/Mld2 adult mice revealed that Erg is required for normal adult HSC homeostasis. HSCs are reduced in number in Erg ϩ/Mld2 mice and unable to compete effectively with Erg ϩ/ϩ cells to reconstitute irradiated transplant recipients (12).In translocations driving Ewing's sarcoma, Fli-1 and Erg appear to be interchangeable; either Fli-1 or Erg can fuse with the gene encoding an RNA binding protein, EWS, and give rise to clinically indistinguishable disease (13). Moreover, in vitro data suggests that Fli-1 and Erg may heterodimerize to regulate sets of overlapping target genes (14, 15), raising the prospect that these proteins may, in part, be redundant. To explore the relationship between Fli-1 and Erg in a physiological setting, w...

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“…The erythroblastosis virus E26 transforming sequence (ETS) encodes the ETS-related gene (ERG) that has an important physiological role in hematopoiesis (Loughran et al, 2008), angiogenesis (Birdsey et al, 2008), vascular (Ellett et al, 2009) and bone development (Iwamoto et al, 2007). ERG belongs to the highly conserved ETS transcription factor family that is defined by the ETS DNA-binding motif 5 0 -GGA(A/T)-3 0 (Sharrocks, 2001;Wei et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

et al. 2011

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E26 transforming sequence-related gene (ERG) is a transcription factor involved in normal hematopoiesis and is dysregulated in leukemia. ERG mRNA overexpression was associated with poor prognosis in a subset of patients with T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Herein, a genome-wide screen of ERG target genes was conducted by chromatin immunoprecipitation-on-chip (ChIP-chip) in Jurkat cells. In this screen, 342 significant annotated genes were derived from this global approach. Notably, ERG-enriched targets included WNT signaling genes: WNT11, WNT2, WNT9A, CCND1 and FZD7. Furthermore, chromatin immunoprecipitation (ChIP) of normal and primary leukemia bone marrow material also confirmed WNT11 as a target of ERG in six of seven patient samples. A larger sampling of patient diagnostic material revealed that ERG and WNT11 mRNA were coexpressed in 80% of AML (n ¼ 30) and 40% in T-ALL (n ¼ 30) bone marrow samples. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. Conversely, in a tet-on ERG-inducible assay, WNT11 transcripts were costimulated. A WNT pathway agonist, 6-bromoindirubin-3-oxime (BIO), was used to determine the effect of cell growth on the ERG-inducible cells. The addition of BIO resulted in an ERG-dependent proliferative growth advantage over ERG-uninduced cells. Finally, ERG induction prompted morphological transformation whereby round unpolarized K562 cells developed elongated protrusions and became polarized. This morphological transformation could effectively be inhibited with BIO and with siRNA knockdown of WNT11. In conclusion, ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Potent ERG induction promoted morphological transformation through WNT11 signals. The findings in this study unravel new ERG-directed molecular signals that may contribute to the resistance of current therapies in acute leukemia patients with poor prognosis characterized by high ERG mRNA expression.

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The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells

Cited by 248 publications

References 54 publications

Two distinct types of murine blast colony-forming cells are multipotential hematopoietic precursors

Two distinct types of murine blast colony-forming cells are multipotential hematopoietic precursors

Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

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