Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1

Chan, David W.; Wilson, Trevor; Xu, Dakang; Cowdery, Helen E; Sanij, Elaine; Hertzog, Paul J.; Kola, Ismail

doi:10.1038/sj.bjc.6600669

Cited by 16 publications

(7 citation statements)

References 40 publications

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“…[65][66][67][68] In a previous CGH study, 38 8q was identified as a frequent site of amplification, above all in 'malignant' GISTs (until 57% of metastatic tumors). We have found amplification of CMYC only in three cases.…”

Section: Discussionmentioning

confidence: 99%

Patterns of gene amplification in gastrointestinal stromal tumors (GIST)

Tornillo

Duchini

Carafa

et al. 2005

Laboratory Investigation

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Gastrointestinal stromal tumors (GIST) are the most common primary mesenchymal tumors of the gastrointestinal tract (GIT). They represent a wide clinico-pathological spectrum of tumors. No single histological or clinical parameter can predict the prognosis while the response to therapy is related to the type of KIT or PDGFRA mutation. Cytogenetic and CGH studies have identified frequent gross chromosomal aberrations but the target genes of these changes are unknown. To determine whether known oncogenes take part in genomic rearrangements and to investigate the potential clinical significance of their amplifications, nine known oncogenes (CMYC, MDM2, GLI1, CDK4, HER2, EGFR1, CCND1, FGF3, EMS) were analyzed by fluorescent in situ hybridization (FISH) on a tissue microarray (TMA) containing 94 primary GIST. Clinical followup information was available for 57 of these patients. Amplification was found for CMYC in three of 90 (3.3%), for MDM2 in five of 94 (5.3%), for EGFR1 in five of 94 (5.3%), and for CCND1 in seven of 79 (8.9%) evaluable cases. No amplifications were seen for HER2, GLI1, CDK4, FGF3, and EMS. Amplifications of MDM2 and CCND1 were associated with clinical and histological malignancy. In conclusion, our data show that gene amplification does occur in a subset of GIST. Identification of MDM2/CCND1 amplification may represent another molecular feature that could help in the evaluation of the behavior of GISTs. Laboratory Investigation (2005) 85, 921-931.

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Section: Discussionmentioning

confidence: 99%

Patterns of gene amplification in gastrointestinal stromal tumors (GIST)

Tornillo

Duchini

Carafa

et al. 2005

Laboratory Investigation

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“…The use of techniques such as antisense oligonucleotides, dominant negative alleles, and transient siRNA transfections have been important preliminary approaches which have aided in this study. [30][31][32][33][34][35][36] However, the pitfalls inherent to these techniques have limited their usefulness. For example, antisense techniques can trigger a growth-inhibitory γ-interferon response due to the formation of double stranded RNA species (Ref.…”

Section: Retroviral Rnai To Study Ews/fli In Ewing's Sarcomamentioning

confidence: 99%

Identification of Target Genes in Their Native Cellular Context

Owen

Lessnick

2006

Cell Cycle

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Ewing's sarcoma is the second most common tumor of bone in children and young adults, and requires highly intensive chemotherapy along with surgery and/or radiation for successful treatment. Because these therapies are associated with significant short- and long-term side effects, new therapeutic approaches are needed. Most cases of Ewing's sarcoma contain somatic translocations between chromosomes 11 and 22 that result in the t(11;22)(q24;q12). This translocation encodes the EWS/FLI fusion protein. EWS/FLI formation appears to be the critical oncogenic event in the development of Ewing's sarcoma. It is hoped that an in-depth understanding of the mechanism that EWS/FLI uses to cause oncogenic transformation will result in new therapies for this disease. Unfortunately, this hope has not been realized. One difficulty has been the lack of an appropriate model system in which to study the fusion oncoprotein. We recently described and validated the use of retroviral RNA interference approaches to study EWS/FLI in Ewing's sarcoma cell lines. We now put this model into a historical context, and describe the benefits (both perceived and observed) of this model over previous approaches using heterologous cell types.

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“…[25][26][27] Interestingly, this phenotype may be reversed by using a transcriptional repressor, which inhibits only the transcriptional activity of EWS/FLI-1, confirming that its oncogenic activity is related to the aberrant expression of specific EWS/FLI-1 target genes. 28 However, since its transforming activity is not only dependent upon the DNA-binding domain, it has been suggested that a protein-protein interaction may represent an additional FLI-1 oncogenetic mechanism. 29 Interestingly, up-regulation of c-myc is observed in the cell lines expressing EWS/FLI-1.…”

Section: Fli-1 Immunoreactivity In Round Cell and Vascular Tumors S Rmentioning

confidence: 99%

Utility of the immunohistochemical detection of FLI-1 expression in round cell and vascular neoplasm using a monoclonal antibody

et al. 2004

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FLI-1 nuclear transcription factor has been proposed as a useful tool in the differential diagnosis of small round cell sarcomas. Recently, FLI-1 has been reported as the first nuclear marker of endothelial differentiation. However, its clinical use has been hampered by major interpretation problems, due to the presence of background staining as well as staining variation between different lots of the same antiserum. In this study, a novel monoclonal antibody raised against the carboxyl terminal of the FLI-1 protein (clone GI146-222, BD Pharmingen) was tested in a series of small round cell and vascular neoplasms. Furthermore, in order to assess FLI-1 specificity, we analyzed its expression in a series of common epithelial and nonepithelial malignancies. In total, 15 Ewing's sarcomas, 10 rhabdomyosarcomas, 5 desmoplastic small round cell tumors, 10 synovial sarcomas, 10 high-grade pleomorphic sarcomas, 10 malignant melanomas, 5 Merkel's carcinomas, 10 colonic adenocarcinomas, 10 breast carcinomas, 10 lung adenocarcinomas, 20 angiosarcomas, 5 epithelioid hemangioendotheliomas, 10 Kaposi's sarcomas and 10 benign hemangiomas, were stained. A strong FLI-1 immunoreactivity was detected in all Ewing's sarcomas and vascular neoplasms, highlighting the high sensitivity of FLI-1 monoclonal antibody. However, 2/5 Merkel's carcinomas and 1/10 malignant melanomas showed a strong nuclear immunostaining, suggesting that FLI-1 may not be so helpful in the differential diagnosis of cutaneous Ewing's sarcoma. In addition, a weak immunoreactivity was found in 3/5 Merkel cell carcinomas, 3/10 synovial sarcomas, 5/10 malignant melanomas, 6/10 lung adenocarcinomas and in 1/10 breast carcinomas. In contrast, all the rhabdomyosarcomas, desmoplastic small round cell tumors, high-grade pleomorphic sarcomas and colonic adenocarcinomas tested were negative. Importantly, in contrast with previous studies, no background staining was observed. Our results indicate that FLI-1 monoclonal antibody can be reliably applied to the differential diagnosis of small round cell neoplasms of soft tissue, and confirm its important role as nuclear marker of endothelial differentiation, mainly helpful in those cases in which technical artifacts are seen by using the traditional membranous and cytoplasmic endothelial markers. 2 The EWS/FLI-1 chimeric protein binds DNA with the same affinity as FLI-1, but EWS/FLI-1 transcriptional activation of the target genes is much more efficient.3 ES/PNET belongs to a heterogeneous group of mesenchymal neoplasms featuring round cell morphology and therefore collectively known as small round cell sarcomas. Alveolar rhabdomyosarcoma (RMS), desmoplastic small round cell tumor (DSRCT), mesenchymal chondrosarcoma and poorly differentiated synovial sarcoma (SS) also belong to

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Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1

Cited by 16 publications

References 40 publications

Patterns of gene amplification in gastrointestinal stromal tumors (GIST)

Patterns of gene amplification in gastrointestinal stromal tumors (GIST)

Identification of Target Genes in Their Native Cellular Context

Utility of the immunohistochemical detection of FLI-1 expression in round cell and vascular neoplasm using a monoclonal antibody

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