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

Nature. 2014 Feb 27;506(7489):451-5. doi: 10.1038/nature13109. Epub 2014 Feb 19.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Base Sequence
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Line
  • Cell Nucleus / metabolism
  • Cell Transformation, Neoplastic* / genetics
  • Chromosomes, Human, Pair 11 / genetics
  • Ependymoma / genetics*
  • Ependymoma / metabolism*
  • Ependymoma / pathology
  • Female
  • Humans
  • Mice
  • Models, Genetic
  • Molecular Sequence Data
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Signal Transduction*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Transcription Factors
  • Translocation, Genetic / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • C11orf95 protein, human
  • NF-kappa B
  • Oncogene Proteins, Fusion
  • Phosphoproteins
  • Proteins
  • RELA protein, human
  • Transcription Factor RelA
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human