RNA-Editing-Initiated MAVS Signaling is a Key Epitranscriptomic Alteration in Human B Cell Lymphoma

Abstract

Diffuse large B cell lymphoma (DLBCL) is one of the most common types of aggressive lymphoid malignancy. Genetically, it is a highly heterogeneous disease. Here, we explore the contribution of an epitranscriptomic modification (RNA editing) to DLBCL pathogenesis. We demonstrate that DNA mutations and RNA editing events are often mutually exclusive, suggesting that tumours can modulate pathway outcomes by altering sequence at either the genomic or the transcriptomic level. We further show that in DLBCL, RNA editing targets transcripts within known disease-driving pathways such as apoptosis, p53 and NF-κB signaling, as well as novel gene targets like MAVS, the essential downstream adaptor of RIG-I-like receptors and a central molecule in the innate response to RNA viruses. We next illustrate that ADAR1-mediated editing in the MAVS transcript correlates with increased MAVS mRNA and protein expression levels. Increased MAVS expression in DLBCL furthermore associates with increased interferon/NF-κB signaling and increased T cell exhaustion. We validate these findings in independent cohorts of DLBCL samples as well as another type of germinal center related B cell lymphoma, follicular lymphoma. Finally, using targeted RNA base editing tools to restore editing specifically within MAVS 3'UTR in ADAR1-deficient cells, we demonstrate that editing is causal to an increase in downstream signaling, in the absence of activation by canonical nucleic acid receptor sensing. Overall, ADAR1-mediated RNA editing represents a new mechanism underlying human B cell lymphomagenesis.