Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours

Delattre, Olivier; Zucman, Jessica; Plougastel, Béatrice; Desmaze, Chantal; Melot, Thomas; Peter, Martine; Kovar, Heinrich; Joubert, Isabelle; Jong, Pieter J. de; Rouleau, Guy A.; Aurias, Alain; Thomas, Gilles

doi:10.1038/359162a0

Cited by 1,651 publications

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“…The Fli-1 gene, a target of insertional dysregulation by Friend erythroleukemia virus was recently found to be rearranged in the Ewing family of tumors carrying t(11;22)(q24;q12) chromosomal translocation (Delattre et al, 1992). The present study is aimed at characterizing the regulatory sequences of the human libraries with erg probe and analysis of the cDNA sequences revealed alternative splicing and the presence of di erent 5'-ends in Fli-1 transcripts (Fli-1 and Fli1b).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, Spi-1 is not found to be rearranged in erythroleukemias induced by F-MuLV nor is Fli-1 shown to be rearranged in SFFV-induced leukemias, suggesting the high speci®city of integration/activation of these genes. Mouse Fli-1 locus has been localized to chromosome 9 and its human homologue to chromosome 11, syntenic with mouse chromosome (Ben-David et al, 1991;Delattre et al, 1992;Baud et al, 1991), frequently involved in rearrangements in many human leukemias, lymphomas and sarcomas (Haluska et al, 1986;Yunis et al, 1986;Selleri et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

“…The Fli-1 gene has been recently shown to be rearranged in a majority of cases of Ewing's family of tumors that share t(11:22) chromosome translocation (Delattre et al, 1992). Molecular characterization of these Ewing family of tumors revealed fusion of the EWS gene on chromosome 22, with either Fli-1 or erg genes located on chromosomes 11 and 21 respectively.…”

Section: Introductionmentioning

confidence: 99%

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Fli-1b is generated by usage of differential splicing and alternative promoter

et al. 1998

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The proto-oncogene Fli-1, a member of Ets family is rearranged or activated through proviral integration in erythroleukemias, induced by Friends' Murine Leukemia Virus. The DNA binding domain (ETS domain) of Fli-1 is fused to the RNA binding domain of EWS by t(11q24:22q12) chromosomal translocation in Ewing's sarcoma and primitive neuroectodermal tumors. Screening of human cDNA libraries has identi®ed two di erent 5'-termini and alternatively spliced forms of the human Fli-1 gene (Fli-1b), suggesting the possible existence of two independent promoters. The genomic sequence adjacent to the alternate exon of human Fli-1b gene shows functional promoter activity when cloned in promoter-less CAT expression vector and transfected into QT-6 cells. The transcription initiation (CAP) site and minimum promoter region necessary for function were localized. The 5'-¯anking regions of human Fli-1b and mouse Fli-1 show 80% homology suggesting conserved promoter regulatory elements. The Fli-1b 5'-anking sequence lacks canonical TATA or CCAAT boxes but contains a partially conserved TATA-like sequence at position 242. Several transcription factor binding sequences like ATF/CREB, E2A-PBX1, EBP, PEA-3, ETS-2, Sp-1, c-Myc, TBP, GATA-1 and Oct-3 were conserved in the promoter sequence. Functional promoter assays revealed that Fli-1b promoter shows very strong transcriptional activation compared to Fli-1 promoter. We also showed that variant Fli-1b has transcriptional activation properties similar to those of Fli-1. Fli-1b and Fli-1 show di erential expression in various hematopoietic cell lines. This di erential expression and promoter activities of Fli-1 and Fli-1b suggests that several mechanisms are involved in Fli-1 gene regulation which are mediated by many transcription factors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fli-1b is generated by usage of differential splicing and alternative promoter

et al. 1998

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“…Ewing sarcoma, a pediatric solid tumor, is uniquely characterized by a speci®c t(11;22)(q24;q12) chromosomal translocation found in over 85% of the cases (Turc-Carel et al, 1988). This genetic alteration generates a novel inframe fusion gene between sequences encoding the Nterminus of the RNA binding protein EWS, and the Cterminus of FLI-1, a member of the ETS family of transcription factors (Delattre et al, 1992). Other less frequent chromosomal translocations involve the same region of EWS and one of several ETS genes; ERG, ETV-1, E1AF, or FEV (Jeon et al, 1995;Peter et al, 1997;Sorensen et al, 1994;Urano et al, 1996).…”

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confidence: 99%

Transforming activity of EWS/FLI is not strictly dependent upon DNA-binding activity

Jaishankar

Roussel

et al. 1999

Oncogene

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In approximately 85% of Ewing sarcomas, chromosomal translocations give rise to the chimeric gene EWS/FLI, encoding the N-terminus of the RNA binding protein EWS fused to the DNA-binding domain of the ETS protein FLI-1. EWS/FLI is a stronger transcriptional activator than wild-type FLI-1, although both proteins bind to the same DNA sequences in vitro. In addition, EWS/FLI, but not FLI-1, is a transforming oncogene in NIH3T3 ®broblasts. EWS/FLI is thought to transform through its ability to deregulate the expression of target genes. We introduced several point mutations into the ETS domain of EWS/FLI that abolished DNA-binding activity. Although two of these mutations disrupted the transforming activity of EWS/FLI, one mutated protein containing a substitution of isoleucine 347 with glutamic acid (I347E) retained diminished transforming activity. In addition, EWS/FLI I347E did not activate expression of the endogenous EWS/FLI target gene manic fringe (MFNG). These studies demonstrate that a portion of the oncogenic activity of EWS/FLI is independent of FLI DNA-binding activity.

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“…In EWS, chromosomal translocation produce fusion gene, EWS/Fli-1 or EWS/ERG, respectively (Delattre et al, 1992;Arvand and Denny, 2001). Fli-1 and ERG gene are members of the erythroblast transformation-specific (ETS) family of transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Ewing's sarcoma fusion protein, EWS/Fli-1 and Fli-1 protein induce PLD2 but not PLD1 gene expression by binding to an ETS domain of 5′ promoter

et al. 2006

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It was reported that short interfering RNA (siRNA) of EWS/Fli-1 downregulated phospholipase D (PLD)2 in Ewing's sarcoma (EWS) cell line, suggesting that PLD2 is the target of aberrant transcription factor, EWS/Fli-1. Here, we further investigated the regulation of PLD2 gene expression by EWS/Fli-1 and Fli-1 in another EWS cell line, and also in EWS/Fli-1-or Fli-1-transfected cell line. EWS/Fli-1-or Fli-1-overexpressed cells showed higher PLD2 but not PLD1 protein expression and enhanced cell proliferation as compared to mock transfectant. The treatment of these cells with 1-butanol or siRNA of PLD2 inhibited cell growth, suggesting the pivotal role of PLD in cell growth promotion. PLD2 but not PLD1 mRNA level was also increased in EWS/Fli-1 or Fli-1-transfectants. After determining the transcription initiation points, we cloned the 5 0 promoter of both PLD1 and PLD2 and analysed promoter activities. Results showed that EWS/ Fli-1 and Fli-1 increase PLD2 gene expression by binding to an erythroblast transformation-specific domain (À126 to À120 bp from the transcription initiation site) of PLD2 promoter, which is the minimal and most powerful region. Electrophoresis mobility shift assay using truncated proteins showed that both DNA-binding domain and trans-activating domain were necessary for the enhanced gene expression of PLD2.

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Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours

Cited by 1,651 publications

References 26 publications

Fli-1b is generated by usage of differential splicing and alternative promoter

Fli-1b is generated by usage of differential splicing and alternative promoter

Transforming activity of EWS/FLI is not strictly dependent upon DNA-binding activity

Ewing's sarcoma fusion protein, EWS/Fli-1 and Fli-1 protein induce PLD2 but not PLD1 gene expression by binding to an ETS domain of 5′ promoter

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