Constitutive BR3 receptor signaling in diffuse, large B-cell lymphomas stabilizes nuclear factor-κB-inducing kinase while activating both canonical and alternative nuclear factor-κB pathways

Aberrant nuclear factor kappa B (NF-kappa B) signaling has been found to be of particular importance in diffuse, large B-cell lymphoma (DLBCL) cell survival and proliferation. Although the canonical NF-kappa B signaling pathway has been studied in some detail, activation of the alternative NF-kappa B pathway in DLBCL is not well characterized. Important insights into the regulation of the alternative NF-kappa B pathway in B lymphocytes has recently revealed the regulatory importance of the survival kinase NIK (NF-kappa B-inducing kinase) in genetically engineered murine models. Our studies demonstrate that both the canonical and alternative NF-kappa B pathways are constitutively activated in DLBCL. We also demonstrate that NIK kinase aberrantly accumulates in DLBCL cells due to constitutive activation of B-cell activation factor (BAFF)-R (BR3) through interaction with autochthonous B-lymphocyte stimulator (BLyS) ligand in DLBCL cells. Activation of BR3 in DLBCL induces recruitment and degradation of tumor necrosis factor receptor-associated factor 3, which results in NIK kinase accumulation, I kappa B alpha phosphorylation, and NF-kappa B p100 processing, thereby resulting in continuous activation of both NF-kappa B pathways in DLBCL cells, leading to autonomous lymphoma cell growth and survival. These results further elucidate mechanisms involved in abnormal NF-kappa B activation in DLBCL, and should contribute to better future therapeutic approaches for patients with DLBCL. (Blood. 2011;117(1):200-210)