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

Gijsbers, L. H.; van Dam, T. P.; de Rooij, M. F. M.; de Wilde, G.; Bende, R. J.; Spaargaren, M.; van Gorp, A.; van Noesel, C. J. M.; Guikema, J. E. J.

doi:10.64898/2026.02.24.707639

bioRxiv · 10.64898/2026.02.24.707639

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

Gijsbers, L. H.·van Dam, T. P.·de Rooij, M. F. M.·de Wilde, G.·Bende, R. J.·Spaargaren, M.·van Gorp, A.·van Noesel, C. J. M.·Guikema, J. E. J.

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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-{kappa}B activity, supporting AIDs 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.

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Gijsbers, L. H., van Dam, T. P., de Rooij, M. F. M., de Wilde, G., Bende, R. J., Spaargaren, M., van Gorp, A., van Noesel, C. J. M., Guikema, J. E. J.. 2026-02-25. AID Shapes Proliferation and Cell-of-Origin-associated Transcriptional Programs in Diffuse Large B-cell Lymphoma. https://doi.org/10.64898/2026.02.24.707639

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