ADAR1-mediated RNA editing promotes B cell lymphomagenesis
Diffuse large B cell lymphoma (DLBCL) is one of the most common types of aggressive lymphoid malignancies. Here, we explore the contribution of an epitranscriptomic modification (RNA editing) to DLBCL pathogenesis. We observed that DNA mutations and RNA editing events are often mutually exclusive, suggesting that tumours can modulate pathway outcomes by altering sequences at either the genomic or the transcriptomic level. RNA editing targets transcripts within known lymphoma-driving pathways such as apoptosis, p53 and NF-kB signaling, as well as the previously unrecognized RIG-I-like pathway. In the latter context we show that ADAR1-mediated editing in the MAVS transcript correlates with increased MAVS protein expression levels, associating with increased interferon/NF-kB signaling and increased T cell exhaustion. Finally, using targeted RNA base editing tools to restore editing within MAVS 3'UTR in ADAR1-deficient cells, we demonstrate that editing is likely to be causal to an increase in downstream signaling, in the absence of activation by canonical nucleic acid receptor sensing. Overall, our results suggest that ADAR-1 mediated RNA editing represents an additional mechanism underlying human B cell lymphomagenesis, complementary to that of DNA mutation.