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.

Ranuncolo SM, Pittaluga S, Evbuomwan MO, Jaffe ES, Lewis BA. Hodgkin lymphoma requires stabilized NIK and constitutive RelB expression for survival. Blood 2012 Sept 11 [Epub ahead of print].