Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma

Crozat, Anne; Åman, Pierre; Mandahl, Nils; Ron, David

doi:10.1038/363640a0

Cited by 826 publications

(659 citation statements)

References 17 publications

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“…5 Myxoid liposarcoma represents 20-30% of all liposarcomas, mostly occurs in young adults, and is characterized by a translocation t(12;16)(q13;p11) or, in a few percent of the cases, a t(12;22)(q13;q12), leading to the chimeric fusion product FUS-DDIT3 or EWSR1-DDIT3, respectively. 25,26 According to the literature, one-third of myxoid liposarcoma patients develop distant metastases, 18,27,28 so effective systemic therapy is needed to improve the prognosis of many patients. Previous studies reported NY-ESO-1 expression in 95-100% of myxoid liposarcomas; these results were based on sample sizes ranging from 25 to 38 cases.…”

Section: Ny-eso-1 In Mesenchymal Tumorsmentioning

confidence: 99%

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

et al. 2015

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New York esophageal squamous cell carcinoma 1 (NY-ESO-1, CTAG1B) is a cancer-testis antigen and currently a focus of several targeted immunotherapeutic strategies. We performed a large-scale immunohistochemical expression study of NY-ESO-1 using tissue microarrays of mesenchymal tumors from three institutions in an international collaboration. A total of 1132 intermediate and malignant and 175 benign mesenchymal lesions were enrolled in this study. Immunohistochemical staining was performed on tissue microarrays using a monoclonal antibody for NY-ESO-1. Among mesenchymal tumors, myxoid liposarcomas showed the highest positivity for NY-ESO-1 (88%), followed by synovial sarcomas (49%), myxofibrosarcomas (35%), and conventional chondrosarcomas (28%). Positivity of NY-ESO-1 in the remaining mesenchymal tumors was consistently low, and no immunoreactivity was observed in benign mesenchymal lesions. On the basis of these findings, nearly 90% of myxoid liposarcomas, as well as a significant proportion of synovial sarcomas, myxofibrosarcomas, and conventional chondrosarcomas are good candidates for immunotherapy targeting NY-ESO-1. Modern Pathology (2015) 28, 587-595; doi:10.1038/modpathol.2014.155; published online 21 November 2014New York esophageal squamous cell carcinoma 1 (NY-ESO-1), encoded by the CTAG1B gene, is a cancer-testis antigen that was identified in 1997 from the serum of a patient with esophageal squamous cell carcinoma. 1 Cancer-testis antigens such as NY-ESO-1 have attracted increasing attention as immunotherapeutic targets because, among normal tissues, they are expressed only in adult testis germ cells and are atypically re-expressed in many malignancies. 2,3 NY-ESO-1 is of particular interest to researchers and clinicians because it is highly immunogenic and is expressed in a variety of carcinomas, melanomas, and sarcomas. 4 A recent clinical trial of adoptive immunotherapy, using genetically modified T cells directed against NY-ESO-1, demonstrated objective clinical responses in a number of metastatic synovial sarcoma and melanoma patients with NY-ESO-1-positive tumors. 5 The results of that clinical trial highlight the potential effectiveness of immunotherapy against tumors expressing NY-ESO-1, and several clinical trials (using antigen sensitization, adoptive T-cell transfer, and dendritic cell vaccine strategies) are currently underway.Mesenchymal tumors arising from bone or soft tissues comprise many histologic subtypes, which even when taken together occur at a much lower rate than the more common carcinomas, creating a practical barrier to developing new drug therapies. However, the well-defined biology of many sarcomas suggests they may be particularly susceptible to appropriate targeted strategies. Recent studies have reported NY-ESO-1 expression in an especially large proportion of myxoid liposarcomas and synovial sarcomas. 2,6-9 These studies also revealed the

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Section: Ny-eso-1 In Mesenchymal Tumorsmentioning

confidence: 99%

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

et al. 2015

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“…CHOP transcripts are present in early blastula stage mouse embryos (Fleming et al, 1997;Fontanier-Razzaq et al, 1999), and the protein plays a role in the differentiation of osteoblasts, keratinocytes, during hematopoesis, and in the control of adipogenesis (Maytin and Habener, 1998;Tang and Lane, 2000;Pereira et al, 2004). In myxoid liposarcoma fusion proteins of CHOP and TLS (translocated in liposarcoma) result in impaired growth arrest and promote malignant transformation of cells during adipogenesis (Crozat et al, 1993;Rabbitts et al, 1993), a process that is normally controlled by Wnt signals (Ross et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

et al. 2006

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CHOP (GADD153) is a protein of the C/EBP family of transcriptional regulators, which dimerizes with other C/EBP members and changes their DNA-binding and transactivation properties. It induces growth arrest and apoptosis after endoplasmatic reticulum stress or DNA damage. CHOP is also expressed during early embryogenesis and upregulated in tumour tissues with defective Wnt signals. We report here that CHOP functions as a specific inhibitor of Wnt/T-cell factor (TCF) signalling. CHOP inhibits TCF-dependent transcription in human embryonic and colon cancer cell lines. Injection of CHOP mRNA into early Xenopus laevis embryos suppresses dorsal organizer formation and inhibits secondary axis formation and TCF-dependent transcription in response to Wnt-8, Dishevelled, b-Catenin and TCF-VP16. In embryos and human cells, this inhibition depends on the N-terminal transactivation domain of CHOP, whereas the C-terminal dimerization domain is dispensable. CHOP binds to TCF factors, thereby preventing the binding of TCF to its DNA recognition site. Our findings demonstrate a novel function of CHOP as a Wnt repressor.

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“…The EWS-Fli1 fusion gene codes for a chimeric protein in which the amino terminal moiety of EWS, which is rich in glutamine, serine and tyrosine residues, is fused to the carboxy-terminal DNA-binding domain (ets domain) of Fli1 (Delattre et al, 1992). EWS was the ®rst member of a growing family of RNA-binding proteins, including TLS/FUS (Zinszner et al, 1994;Rabbitts et al, 1993;Crozat et al, 1993), hTAF II 68 (Bertolotti et al, 1996), the snRNP associated 69 KD protein (Hackl and Luhrmann, 1996), the bovine Pigpen protein (Alliegro and Alliegro, 1996) and Drosophila Cabeza/SARFH (Stolow and Haynes, 1995;Immanuel et al, 1995), that share distinct structural characteristics in their carboxy termini, such as an RNP motif, RGG boxes and a putative zinc-®nger domain. However, its biological functions largely remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II

et al. 1998

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As a result of the t(11;22)(q24;q12) chromosomal translocation characterizing the Ewing family of tumors (ET), the amino terminal portion of EWS, an RNA binding protein of unknown function, is fused to the DNA-binding domain of the ets transcription factor Fli1. The hybrid EWS-Fli1 protein acts as a strong transcriptional activator and, in contrast to wildtype Fli1, is a potent transforming agent. Similar rearrangements involving EWS or the highly homologous TLS with various transcription factors have been found in several types of human tumors. Employing yeast twohybrid cloning we isolated the seventh largest subunit of human RNA polymerase II (hsRPB7) as a protein that speci®cally interacts with the amino terminus of EWS. This association was con®rmed by in vitro immunocoprecipitation. In nuclear extracts, hsRPB7 was found to copurify with EWS-Fli1 but not with Fli1. Overexpression of recombinant hsRPB7 speci®cally increased gene activation by EWS-chimeric transcription factors. Replacement of the EWS portion by hsRPB7 in the oncogenic fusion protein restored the transactivating potential of the chimera. Our results suggest that the interaction of the amino terminus of EWS with hsRPB7 contributes to the transactivation function of EWS-Fli1 and, since hsRPB7 has characteristics of a regulatory subunit of RNA polymerase II, may in¯uence promoter selectivity.

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Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma

Cited by 826 publications

References 17 publications

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II

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