Brain Tumor by NF-κB Fusion

Science Signaling  04 Mar 2014:
Vol. 7, Issue 315, pp. ec61
DOI: 10.1126/scisignal.2005230

Although increased signaling through the nuclear factor κB (NF-κB) pathway is associated with many cancers, mutations affecting this pathway are uncommon. Parker et al. performed whole-genome analysis of ependymomas (a type of brain tumor arising from neural stem cells) and identified chromosomal translocations involving RELA, encoding a subunit of the transcription factor NF-κB, and C11orf95, a poorly characterized gene that has been observed fused to another transcription factor–encoding gene in lipoma. The presence of the fusion protein transcript and protein were confirmed in several tumors, and the translocation event occurred only in tumors located in brain regions above the cerebellum (supratentorial). Both wild-type RELA and four C11orf95-RELA fusion proteins, resulting from alternative splicing of the fusion transcript, were detected in supratentorial ependymoma ST3 cells, but the fusion protein exhibited preferential accumulation in the nucleus. Expression of wild-type RELA (RELAWT) or one of the C11orf95-RELA fusion proteins (RELAFUS1) in 293T cells showed that, whereas endogenous RELA required a stimulus to activate an NF-κB reporter gene, RELAFUS1, even expressed at amounts similar to endogenous RELA, translocated to the nucleus and activated the reporter constitutively. Microarray analysis showed that introduction of RELAFUS1 or RELAWT into mouse neural stem cells (NSCs), but not introduction of C11orf95, resulted in activation of an NF-κB transcriptional profile with the fusion protein producing greater activation than the wild-type RELA. Mouse cerebral implantation of NSCs expressing red fluorescent protein–tagged versions of RELAWT, RELAFUS1, or RELAFUS2 showed that the fusion proteins were oncogenic and resulted in the formation of tumors with morphological characteristics of ependymoma and with activated and nuclear localized fusion protein. YAP1 is another transcription factor that was found in some of the tumors as a fusion protein with C11orf95 due to chromosomal translocation, and NSCs expressing this fusion protein also formed tumors. Thus, fusion of C11orf95, which has zinc finger domains, to other transcriptional regulators appears to drive oncogenesis.

M. Parker, K. M. Mohankumar, C. Punchihewa, R. Weinlich, J. D. Dalton, Y. Li, R. Lee, R. G. Tatevossian, T. N. Phoenix, R. Thiruvenkatam, E. White, B. Tang, W. Orisme, K. Gupta, M. Rusch, X. Chen, Y. Li, P. Nagahawhatte, E. Hedlund, D. Finkelstein, G. Wu, S. Shurtleff, J. Easton, K. Boggs, D. Yergeau, B. Vadodaria, H. L. Mulder, J. Becksford, P. Gupta, R. Huether, J. Ma, G. Song, A. Gajjar, T. Merchant, F. Boop, A. A. Smith, L. Ding, C. Lu, K. Ochoa, D. Zhao, R. S. Fulton, L. L. Fulton, E. R. Mardis, R. K. Wilson, J. R. Downing, D. R. Green, J. Zhang, D. W. Ellison, R. J. Gilbertson, C11orf95–RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 506, 451–455 (2014). [PubMed]