The alternative RelB NF-κB subunit is a novel critical player in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy affecting adults. The NF-κB transcription factor family is activated by 2 main pathways, the canonical and the alternative NF-κB activation pathway, with different functions. The alternative NF-κB pathway leads to activation of the transcriptionally active RelB NF-κB subunit. Alternative NF-κB activation status and its role in DLBCL pathogenesis remain undefined. Here, we reveal a frequent activation of RelB in a large cohort of DLBCL patients and cell lines, independently of their activated B-cell-like or germinal center B-cell-like subtype. RelB activity defines a new subset of patients with DLBCL and a peculiar gene expression profile and mutational pattern. Importantly, RelB activation does not correlate with the MCD genetic subtype, enriched for activated B-cell-like tumors carrying MYD88L265P and CD79B mutations that cooperatively activate canonical NF-κB, thus indicating that current genetic tools to evaluate NF-κB activity in DLBCL do not provide information on the alternative NF-κB activation. Furthermore, the newly defined RelB-positive subgroup of patients with DLBCL exhibits a dismal outcome after immunochemotherapy. Functional studies revealed that RelB confers DLBCL cell resistance to DNA damage-induced apoptosis in response to doxorubicin, a genotoxic agent used in the front-line treatment of DLBCL. We also show that RelB positivity is associated with high expression of cellular inhibitor of apoptosis protein 2 (cIAP2). Altogether, RelB activation can be used to refine the prognostic stratification of DLBCL and may contribute to subvert the therapeutic DNA damage response in a segment of patients with DLBCL. © 2022 by The American Society of Hematology.

Citation

Baptiste Eluard, Stéphanie Nuan-Aliman, Nathalie Faumont, Davi Collares, Didier Bordereaux, Aurélie Montagne, Isabelle Martins, Nicolas Cagnard, Martial Caly, Oussama Taoui, Leonardo Lordello, Jacqueline Lehmann-Che, Bruno Tesson, Jose-Angel Martinez-Climent, Christiane Copie-Bergman, Corinne Haioun, Hervé Tilly, Benjamin Bonsang, Anne Vincent-Salomon, Jean-Philippe Jais, Fabrice Jardin, Karen Leroy, Maria Chiara Maiuri, Guido Kroemer, Thierry Jo Molina, Jean Feuillard, Véronique Baud. The alternative RelB NF-κB subunit is a novel critical player in diffuse large B-cell lymphoma. Blood. 2022 Jan 20;139(3):384-398

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PMID: 34232979

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