The Oncogenic TLS-ERG Fusion Protein Exerts Different Effects in Hematopoietic Cells and Fibroblasts

Zou, Jie; Ichikawa, Hitoshi; Blackburn, Michael L.; Hu, Hsien-Ming; Zielinska-Kwiatkowska, Anna; Mei, Qi; Roth, Gerald J.; Chansky, Howard A.; Yang, Liu

doi:10.1128/mcb.25.14.6235-6246.2005

Cited by 19 publications

(19 citation statements)

References 37 publications

(59 reference statements)

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“…Further, this result is consistent with the substantial discordance found in the gene expression programs induced by overexpression of ERG fusion proteins (TLS-ERG and EWS-ETS) in different cell lines (11,12).…”

Section: Erg Expression Produces An Invasive Phenotype Mediated By Sesupporting

confidence: 77%

A causal role for ERG in neoplastic transformation of prostate epithelium

Klezovitch

Risk

Coleman

et al. 2008

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

275

256

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A significant proportion of human prostate cancers carry a chromosomal rearrangement resulting in the overexpression of the ETS transcription factor, ERG; however, the functional significance of this event is poorly understood. We report here that up-regulation of ERG transcript is sufficient for the initiation of prostate neoplasia. In agreement with measurements of ERG transcripts, we found that ERG protein is expressed in neoplastic human prostate epithelium. Overexpression of ERG in prostate cell lines increased cell invasion. Moreover, targeted expression of this transcript in vivo in luminal prostate epithelial cells of transgenic mice results in initiation of prostate neoplasia observed as the development of focal precancerous prostatic intraepithelial neoplasia (PIN). Similar to human cancers, luminal epithelial cells in these PIN lesions displace diminishing in numbers basal epithelial cells and establish direct contact with the stromal cell compartment. Loss of basal cells is considered to be one of the critical hallmarks of human prostate cancer; however, the mechanisms responsible for this event were unknown. We propose that up-regulation of ERG in human prostate cancer activates cell invasion programs that subsequently displace basal cells by neoplastic epithelium. Our data demonstrate that ERG plays an important causal role in the transformation of prostate epithelium and should be considered as a target for prevention or early therapeutic intervention.mouse models ͉ prostate cancer ͉ prostatic intrepithelial neoplasia (PIN) ͉ ETS family A n outlier identification approach for the analysis of transcript profiles recently identified recurrent chromosomal rearrangements in human prostate cancer (1). Fusion events joining the androgen-responsive TMPRSS2 gene and members of the erythroblastosis virus E26 oncogene (ETS) family result in the overexpression of a N-terminally truncated or full-length forms of the ERG transcription factor (⌬N-ERG and ERG). Subsequent studies have confirmed that TMPRSS2-ERG fusion is a common genetic event that occurs early in prostate carcinogenesis at the transition between benign and prostatic intraepithelial neoplasia (PIN) epithelium (2). This rearrangement has been correlated with tumor metastasis and negative patient outcome (3, 4). To determine the role of ERG overexpression in prostate carcinogenesis, we modeled this alteration in prostate epithelial cells in culture and in mouse prostate epithelium in vivo. We report that up-regulation of ERG activates prostate cell invasion and results in the displacement of prostate basal epithelium by the luminal cells and the development of PIN. Results ERG Expression Produces an Invasive Phenotype Mediated by SerineProtease Activity. Transcript profiling studies have demonstrated overexpression of the ERG transcription factor in the majority of human primary prostate cancers (5). To determine the presence, cell type specificity of expression, and intracellular localization of ERG protein we performed immunofluorescent staining...

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Section: Erg Expression Produces An Invasive Phenotype Mediated By Sesupporting

confidence: 77%

A causal role for ERG in neoplastic transformation of prostate epithelium

Klezovitch

Risk

Coleman

et al. 2008

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

275

256

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“…As the differentiated phenotypes of the associated cancers differ, the fusion does not appear to provide a common set of differentiation instructions. These observations are consistent with the finding of significant differences in downstream expression modulated by these fusion proteins in different cellular environments (10). However, other experiments show that some fusion proteins can program an unrelated cell type to differentiate along a specific pathway (11).…”

supporting

confidence: 82%

The Impact of Genetics on Sarcoma Diagnosis: An Evolving Science

Barr

Zhang

2006

Clinical Cancer Research

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“…TLS-ERG has been reported to affect both gene transcription and RNA splicing by several groups in fibroblasts and in hematopoietic cells (5,6). Our recent studies further suggested that transformation of L-G myeloid progenitor cells by TLS-ERG is likely to be associated with a repressive effect of the fusion protein on gene transcription (7). Leukemia cells are characterized by an advantage in proliferation and an arrest of differentiation at various stages of hematopoiesis.…”

Section: Introductionmentioning

confidence: 99%

“…Our recent studies have suggested that TLS-ERG transformation of L-G myeloid progenitor cells is likely associated with a repressive effect of the fusion protein on gene transcription (7). Silencing of genes critical to myeloid differentiation is a well-known phenomenon associated with leukemia fusion proteins.…”

Section: Epigenetic Drugs Down-regulate Cdk1 and Promote Differentiatmentioning

confidence: 99%

TLS-ERG Leukemia Fusion Protein Deregulates Cyclin-Dependent Kinase 1 and Blocks Terminal Differentiation of Myeloid Progenitor Cells

Pan

Zou

Wu³

et al. 2008

Molecular Cancer Research

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TLS-ERG fusion protein is derived from the t(16;21) translocation found in human myeloid leukemia. Here, we show that retroviral transduction of TLS-ERG confers a growth advantage to L-G myeloid progenitor cells and blocks terminal differentiation. We found that the level of cyclin-dependent kinase 1 (Cdk1) protein was significantly decreased in controls but unchanged in TLS-ERG -expressing cells after granulocyte colony-stimulating factor treatment or interleukin-3 withdrawal. Injection of TLS-ERG -expressing L-G cells induced rapid development of a leukemia-like disease in syngeneic mice. Through site-directed mutagenesis, we showed that transformation and deregulation of Cdk1 by TLS-ERG require an intact ets DNA-binding domain within the fusion protein. Interestingly, treatment of TLS-ERG -expressing L-G cells with 5-aza-2 ¶-deoxycytidine (Decitabine) or trichostatin A resulted in down-regulation of Cdk1 and induction of terminal differentiation. To investigate whether Cdk1 deregulation is indeed responsible for transformation by TLS-ERG, we constructed lentiviral vectors for delivery of Cdk1 mutants and small interfering RNA (siRNA). Both dominant-negative inhibition and siRNA knockdown of Cdk1 were able to restore the ability of TLS-ERG -expressing L-G cells to undergo terminal differentiation. In addition, siRNA knockdown of Cdk1 in YNH-1 cells derived from a t(16;21) acute myelogenous leukemia patient also resulted in terminal differentiation. As restoration of terminal myeloid differentiation to TLS-ERG cells is dependent on cell cycle arrest, our findings suggest an important role for Cdk1 in cellular transformation and may be useful in the search for new treatments of TLS-ERG -associated myeloid leukemia. (Mol Cancer Res 2008;6(5):862 -72)

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The Oncogenic TLS-ERG Fusion Protein Exerts Different Effects in Hematopoietic Cells and Fibroblasts

Cited by 19 publications

References 37 publications

A causal role for ERG in neoplastic transformation of prostate epithelium

A causal role for ERG in neoplastic transformation of prostate epithelium

The Impact of Genetics on Sarcoma Diagnosis: An Evolving Science

TLS-ERG Leukemia Fusion Protein Deregulates Cyclin-Dependent Kinase 1 and Blocks Terminal Differentiation of Myeloid Progenitor Cells

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