C11orf95–RELA fusions drive oncogenic NF-κB signalling in ependymoma

Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aber...

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Vydáno v:	Nature (London) Ročník 506; číslo 7489; s. 451 - 455
Hlavní autoři:	Parker, Matthew, Mohankumar, Kumarasamypet M., Punchihewa, Chandanamali, Weinlich, Ricardo, Dalton, James D., Li, Yongjin, Lee, Ryan, Tatevossian, Ruth G., Phoenix, Timothy N., Thiruvenkatam, Radhika, White, Elsie, Tang, Bo, Orisme, Wilda, Gupta, Kirti, Rusch, Michael, Chen, Xiang, Li, Yuxin, Nagahawhatte, Panduka, Hedlund, Erin, Finkelstein, David, Wu, Gang, Shurtleff, Sheila, Easton, John, Boggs, Kristy, Yergeau, Donald, Vadodaria, Bhavin, Mulder, Heather L., Becksfort, Jared, Gupta, Pankaj, Huether, Robert, Ma, Jing, Song, Guangchun, Gajjar, Amar, Merchant, Thomas, Boop, Frederick, Smith, Amy A., Ding, Li, Lu, Charles, Ochoa, Kerri, Zhao, David, Fulton, Robert S., Fulton, Lucinda L., Mardis, Elaine R., Wilson, Richard K., Downing, James R., Green, Douglas R., Zhang, Jinghui, Ellison, David W., Gilbertson, Richard J.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 27.02.2014 Nature Publishing Group
Témata:	45/100 45/23 45/61 45/77 59/5 631/67/1922 631/67/68 64/60 Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Animals Base Sequence Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - pathology Cancer Carcinogenesis Cell Line Cell Nucleus - metabolism Cell Transformation, Neoplastic - genetics Chromosomes, Human, Pair 11 - genetics Ependymoma - genetics Ependymoma - metabolism Ependymoma - pathology Female Genetic regulation Gliomas Humanities and Social Sciences Humans Mice Models, Genetic Molecular Sequence Data multidisciplinary Neural Stem Cells - metabolism Neural Stem Cells - pathology NF-kappa B - genetics NF-kappa B - metabolism Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Oncogenes Oncology, Experimental Phosphoproteins - genetics Phosphoproteins - metabolism Proteins - genetics Proteins - metabolism Science Signal Transduction Transcription Factor RelA - genetics Transcription Factor RelA - metabolism Transcription Factors Translocation, Genetic - genetics
ISSN:	0028-0836, 1476-4687, 1476-4687
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Shrnutí:	Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA , the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95 . In each case, C11orf95 – RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95–RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95–RELA fusion protein as a potential therapeutic target in supratentorial ependymoma. At least two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA , the principal effector of nuclear factor-κB (NF-κB) signalling, and uncharacterized gene C11orf95 ; C11orf95–RELA fusion proteins translocate spontaneously to the nucleus to activate NF-κB target genes, and rapidly transform neural stem cells to form tumours in mice Genomic analyses of childhood ependymomas In this issue of Nature two groups present independent genomic analyses on ependymomas, a type of tumour that occurs throughout the nervous system, but most commonly in the hindbrain in children. Mack et al . found a low overall mutation rate and no significant recurrent mutations in 47 hindbrain ependymomas. But posterior fossa group B tumours, a subgroup found predominantly in infants and associated with poor prognosis, were distinguished by a CpG island methylator phenotype. This subgroup is shown to be susceptible to various compounds that target epigenetic modifications, including an EZH2 inhibitor that showed efficacy in a mouse xenograft model. Parker et al . found the C11orf95–RELA fusion gene in about 70% of supratentorial tumours, but not in other ependymoma subgroups. The gene fusions arise through chromothripsis and lead to the expression of a fusion protein that constitutively activates NF-κB signalling. In a mouse model, expression of C11orf95–RELA in neural stem cells leads to the formation of brain tumours. These findings identify NF-κB signalling as a possible therapeutic target in patients with this type of ependymoma.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to the work.
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/nature13109