Diversification at the transcriptome 3'end through alternative polyadenylation (APA) is an important and evolutionarily conserved layer of gene regulation associated with differentiation and dedifferentiation processes. Here we identify extensive transcriptome-3'end-alterations in neuroblastoma, a tumour entity with a general paucity of recurrent somatic mutations and an unusually high frequency of spontaneous regression. In an extensive RNAi-screening we reveal the landscape and drivers of transcriptome-3'end-diversification. We discover PCF11 as critical regulator of transcriptome-3'end-diversification, directing APA of hundreds of transcripts including a differentiation RNA-operon. PCF11 shapes inputs converging on WNT-signalling, and governs cell cycle, proliferation, apoptosis and neurodifferentiation. Postnatal PCF11 down-regulation induces a neurodifferentiation program, and low-level PCF11 in neuroblastoma is associated with favourable outcome and spontaneous tumour regression. Our findings document a critical role for APA in tumourigenesis and describe a novel mechanism for cell fate reprogramming in neuroblastoma with important clinical implications. An interactive data repository of transcriptome-wide APA covering >170 RNAis, and an APA-network map with regulatory hubs, is provided.

PCF11 connects alternative polyadenylation to formation and spontaneous regression of neuroblastoma