Splicing-sensitive fusion transcripts associated with key tumor characteristics occur at high frequency in neuroblastoma
Shi, Y.; Rraklli, V.; Maxymovitz, E.; Li, S.; Westerlund, I.; Reina, O. B.; Yuan, J.; Bullova, P.; Juhlin, C. C.; Stenman, A.; Larsson, C.; Kogner, P.; O'Sullivan, M. J.; Schlisio, S.; Holmberg, J.
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The paucity of recurrent mutations has hampered efforts to understand and treat neuroblastoma. Alternative splicing and splicing-dependent RNA-fusions represent mechanisms able to increase the gene product repertoire but their role in neuroblastoma remains largely unexplored. Through analysis of RNA-sequenced neuroblastoma we here show that elevated expression of splicing factors is a strong predictor of poor clinical outcome. Furthermore, we identified >900 primarily intrachromosomal fusions containing canonical splicing sites. Fusions included transcripts from well-known oncogenes, were enriched for proximal genes and in chromosomal regions commonly gained or lost in neuroblastoma. As a proof-of-principle that these fusions can generate altered gene products, we characterized a ZNF451-BAG2 fusion, generating a truncated BAG2-protein which inhibited retinoic acid-induced differentiation. Spliceosome inhibition impeded neuroblastoma fusion expression, induced apoptosis and inhibited xenograft tumor growth. Our findings elucidate a splicing-dependent mechanism producing altered gene products in neuroblastoma and suggest that the spliceosome is a tractable therapeutical target.
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