Enhancer lncRNA LOC730338 limits the innate immune response against lymphoma cells, inhibiting ADAR2-dependent alternative transcription

Chronic antigenic stimulation is central to marginal zone lymphoma (MZL) development. While the pharmacological inhibition of the B-cell receptor (BCR) signaling is initially effective, secondary resistance frequently develops. We conducted a CRISPR interference (CRISPRi) screen investigating enhancer-associated long non-coding RNAs (elncRNAs) in MZL cells to identify transcripts crucial to shape their dependence on BCR pathway activation. We identified LOC730338, an elncRNA associated with A-to-I RNA editing, which we renamed ADARreg. Silencing ADARreg re-sensitized tumor cells to BCR pathway inhibition by modulating ADAR2 nuclear translocation and altering intronic RNA editing. The process preferentially affected genes that enhance immune responses, such as STING, IRF3, and p65. ADARreg knockdown also increased lymphoma cell sensitivity to NK cell-mediated cytotoxicity. Our results indicate that targeting elncRNAs like ADARreg represents a potential strategy to overcome drug resistance in lymphoma, also opening new therapeutic opportunities for immunotherapy.