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

雷布 弥漫性大B细胞淋巴瘤 癌症研究 生物 淋巴瘤 NF-κB 生发中心 B细胞 P50页 免疫学 细胞凋亡 转录因子 遗传学 基因 抗体
作者
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,José A. Martinez‐Climent,Christiane Copie‐Bergman,Corinne Haïoun,Hervé Tilly,B. Bonsang,Anne Vincent‐Salomon,Jean‐Philippe Jaïs,Fabrice Jardin,Karen Leroy,Maria Chiara Maiuri,Guido Kroemer,Thierry Jo Molina,Jean Feuillard,Jacques Ghysdael
出处
期刊:Blood [Elsevier BV]
卷期号:139 (3): 384-398 被引量:33
标识
DOI:10.1182/blood.2020010039
摘要

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.
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