Noncanonical NF-κB signaling is required for Hodgkin lymphoma, but not other B-cell lymphomas.
Major finding: Noncanonical NF-κB signaling is required for Hodgkin lymphoma, but not other B-cell lymphomas.
Mechanism: RelB promotes NIK stabilization by inhibiting expression of the negative regulator, TRAF2.
Impact: Inhibition of NIK activity may selectively suppress Hodgkin lymphoma growth.
Mutation or amplification of the genes encoding the v-rel reticuloendotheliosis viral oncogene homolog (Rel) subfamily of NF-κB proteins, particularly c-Rel and RelA, is found in Hodgkin lymphoma, suggesting a functional role for canonical NF-κB signaling in this disease. In contrast, little is known about the role of the noncanonical NF-κB pathway, which is activated by stabilization of NF-κB inducing kinase (NIK, encoded by MAP3K14) and nuclear localization of NF-κB2 (p52)/RelB heterodimers, in Hodgkin lymphoma. To investigate the relative contributions of Rel proteins, Ranuncolo and colleagues used short hairpin RNAs to downregulate Rel expression in Hodgkin lymphoma and other B-cell lymphoma cell lines, such as mantle cell and diffuse large B-cell lymphoma. Interestingly, RelB depletion specifically reduced the viability of Hodgkin lymphoma cell lines, but not other B-cell lymphomas, suggesting that Hodgkin lymphoma is uniquely dependent on noncanonical NF-κB signaling. The viability of Hodgkin lymphoma cell lines was also diminished upon loss of RelA or c-Rel, supporting nonredundant functions of Rel proteins in promoting tumor growth. In addition, unlike other B-cell lymphoma cells, both Hodgkin lymphoma cell lines and primary Hodgkin lymphoma biopsies exhibited accumulation of NIK protein, indicative of noncanonical NF-κB activity, and NIK downregulation impaired the viability of these Hodgkin lymphoma cell lines. NIK stabilization was mediated by decreased expression of the negative regulator TNF receptor-associated factor 2 (TRAF2); knockdown of RelB or NIK induced TRAF2 expression, suggesting that RelB represses TRAF2 as part of a positive autoregulatory feedback loop. Importantly, treatment with a small-molecule NIK inhibitor was sufficient to selectively reduce the survival of Hodgkin lymphoma cell lines. These results identify a role for noncanonical NF-κB signaling in Hodgkin lymphoma and suggest that targeting this pathway through NIK inhibition may be therapeutically beneficial.