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

Resumen:
Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy affecting adults. The NF-kappa B transcription factor family is activated by 2 main pathways, the canonical and the alternative NF-kappa B activation pathway, with different functions. The alternative NF-kappa B pathway leads to activation of the transcriptionally active RelB NF-kappa B subunit. Alternative NF-kappa B 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 MYD88(L265P) and CD79B mutations that cooperatively activate canonical NF-kappa B, thus indicating that current genetic tools to evaluate NF-kappa B activity in DLBCL do not provide information on the alternative NF-kappa B 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.