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

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy affecting adults. NF-kB transcription factor family is activated by two main pathways, the canonical and the alternative NF-kB activation pathways with different functions. The alternative NF-kB pathway leads to the activation of the transcriptionally active RelB NF-kB subunit. Alternative NF-kB 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 ABC or GCB subtypes. RelB activity defines a new subset of DLBCL patients with a peculiar gene expression profile and mutational pattern. Importantly, RelB activation does not correlate with the MCD genetic subtype, enriched for ABC tumors carrying MYD88L265P and CD79B mutations that cooperatively activate canonical NF-kB, thus indicating that current genetic tools to evaluate NF-kB activity in DLBCL do not provide information on the alternative NF-kB activation. Further, the newly defined RelB-positive subgroup of DLBCL patients exhibits a dismal outcome following immunochemotherapy. Functional studies revealed that RelB confers DLBCL cell resistance to DNA-damage induced apoptosis in response to doxorubicin, a genotoxic agent used in front-line treatment for DLBCL. We also show that RelB positivity is associated with high expression of 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 DLBCL patients.

The Alternative RelB NF-kB Subunit Exerts a Critical Survival Function upon Metabolic Stress in Diffuse Large B-Cell Lymphoma-Derived Cells

“…Frequent mutations in regulators of the classical NF-κB pathway (MYD88, TNFAIP3, CD79A/B, CARD11) are recognized as a hallmark of ABC DLBCL patients [ 19 , 20 , 21 , 22 , 23 ], and inhibition of the classical NF-κB pathway induces cell death in ABC DLBCL cell lines [ 24 ]. Recently, our laboratory has uncovered that the alternative RelB NF-κB subunit is frequently activated in DLBCL patients and cell lines, independently of their ABC or GCB subtypes [ 25 ]. Most importantly, RelB activity predicted worse overall survival upon immunochemotherapy [ 25 ].…”

“…Recently, our laboratory has uncovered that the alternative RelB NF-κB subunit is frequently activated in DLBCL patients and cell lines, independently of their ABC or GCB subtypes [ 25 ]. Most importantly, RelB activity predicted worse overall survival upon immunochemotherapy [ 25 ]. Further, we shed light on a new role for RelB in promoting DLBCL cell survival upon treatment with genotoxic agents [ 25 ].…”

“…Most importantly, RelB activity predicted worse overall survival upon immunochemotherapy [ 25 ]. Further, we shed light on a new role for RelB in promoting DLBCL cell survival upon treatment with genotoxic agents [ 25 ]. Beside the significant advances in the understanding of RelB function in DLBCL, whether RelB activation might be connected to the OxPhos metabolic status of DLBCL cells is still unknown.…”

NF‐κB signaling in inflammation and cancer

“…It was also found that loss‐of‐function mutations of CYLD, A20, TRAF3, and other negative regulators also cause abnormal activation of NF‐κB. 296 , 297 , 298 , 299 , 300 , 301 Similarly, TNFα coded by an NF‐κB target gene TNFA acts as a strong activator of NF‐κB, functions in many tumor cells with constitutive activation of NF‐κB in an autocrine manner (usually stromal). 301 , 302 Taking specific tumor types as an example, DLBCL is the most studied malignant tumor with NF‐κB mutation.…”

“…Meanwhile, the abnormal activation of the noncanonical NF‐κB pathway is also detected more in other DLBCL subtypes. 299 , 300 The mutations in the NF‐κB signaling pathway involved in cancers are summarized in Table 1 .…”