AID Shapes Proliferation and Cell-of-Origin-associated Transcriptional Programs in Diffuse Large B-cell Lymphoma

ABSTRACT Activation-induced cytidine deaminase (AID), which is essential for antibody diversification, exhibits elevated expression in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Here, we demonstrate that AID modulates transcriptional programs linked to cell cycle progression, proliferation, and DLBCL subtype identity. AID loss in ABC-type DLBCL cell lines negatively impacts MYC and E2F pathway activity, while AID re-expression restores activity, establishing a causal link. Consequently, loss of AID delays G1/S cell cycle transition and reduces proliferation. In addition, AID expression skews transcriptional programs towards ABC-type DLBCL in cell lines. In agreement, AID expression correlates with ABC-type gene expression in primary DLBCL patient samples. Moreover, AID overexpression resulted in increased IRF4 protein levels, and enhanced NF-κB activity, supporting AID’s role in reinforcing the ABC-type identity. Shared enrichment of the IRF4 co-factor BATF in AID-high tumors of both ABC- and GCB-subtypes points towards a common mechanism driving subtype skewing. These findings underscore a broader role for AID in DLBCL pathogenesis, establishing AID as a key regulator of transcriptional programs linked to cell cycle progression and DLBCL subtype.