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The alternative RelB NF-κB subunit is a novel critical player in diffuse large B-cell lymphoma
- Source :
- Blood. 139(3)
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Transcriptional Activation
DNA damage
Immunology
Apoptosis
Biology
Biochemistry
chemistry.chemical_compound
immune system diseases
hemic and lymphatic diseases
Cell Line, Tumor
Gene expression
medicine
Humans
Transcription factor
RELB
Transcription Factor RelB
NF-kappa B
NF-κB
Cell Biology
Hematology
CD79B
medicine.disease
Lymphoma
Gene Expression Regulation, Neoplastic
chemistry
Cancer research
Lymphoma, Large B-Cell, Diffuse
Diffuse large B-cell lymphoma
Subjects
Details
- ISSN :
- 15280020
- Volume :
- 139
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....aff6ed9c408fd528e6ce177771a39ed0