Alternative splicing in neuroblastoma generates RNA-fusion transcripts and is associated with vulnerability to spliceosome inhibitors

Abstract

28The paucity of recurrent mutations has hampered efforts to understand the pathogenesis of 29 neuroblastoma. Through analysis of RNA-sequenced neuroblastoma, we identified >900 primarily 30 intrachromosomal fusion transcripts generated by genes in close proximity. Fusions were enriched 31 in chromosomal regions gained or lost in neuroblastoma and included well-known neuroblastoma 32 oncogenes. The majority of fusions contained canonical splicing sites and a subset exhibited 33 increased sensitivity to spliceosome inhibition. As a proof-of-principle that a gene product with 34 altered properties can be produced by these fusions, we characterized the ZNF451-BAG2 fusion 35 which generates a truncated BAG2-protein capable of inhibiting retinoic acid-induced 36 differentiation. Our findings elucidate a mechanism through which altered gene products, relevant 37 for neuroblastoma pathogenesis and representing possible novel drug targets, can be generated. 38 39 413