TRAF3 loss-of-function reveals the noncanonical NF-κB pathway as a therapeutic target in diffuse large B cell lymphoma
Michael Y. Li, Lauren C. Chong, Gerben Duns, Andrew Lytle, Bruce W. Woolcock, Aixiang Jiang, Adèle Telenius, Susana Ben‐Neriah, Waqas Nawaz, Graham W. Slack, Ingrid Elisia, Elena Viganò, Tomohiro Aoki, Shannon Healy, Gerald Krystal, Leandro Venturutti, David W. Scott, Christian Steidl
Abstract
Here, we report recurrent focal deletions of the chr14q32.31-32 locus, including TRAF3 , a negative regulator of NF-κB signaling, in de novo diffuse large B cell lymphoma (DLBCL) (24/324 cases). Integrative analysis revealed an association between TRAF3 copy number loss with accumulation of NIK, the central noncanonical (NC) NF-κB kinase, and increased NC NF-κB pathway activity. Accordingly, TRAF3 genetic ablation in isogenic DLBCL model systems caused upregulation of NIK and enhanced NC NF-κB downstream signaling. Knockdown or pharmacological inhibition of NIK in TRAF3-deficient cells differentially impaired their proliferation and survival, suggesting an acquired onco-addiction to NC NF-κB. TRAF3 ablation also led to exacerbated secretion of the immunosuppressive cytokine IL-10. Coculturing of TRAF3-deficient DLBCL cells with CD8+ T cells impaired the induction of Granzyme B and interferon (IFN) γ, which were restored following neutralization of IL-10. Our findings corroborate a direct relationship between TRAF3 genetic alterations and NC NF-κB activation, and highlight NIK as a potential therapeutic target in a defined subset of DLBCL.