TRAF3 loss- of- function reveals the noncanonical NF- ?B pathway as a therapeutic target in diffuse large B cell lymphoma.

Here, we report recurrent focal deletions of the chr14q32.31- 32 locus, including TRAF3, a negative regulator of NF- kB 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- kB kinase, and increased NC NF- kB pathway activity. Accordingly, TRAF3 genetic ablation in isogenic DLBCL model systems caused upregulation of NIK and enhanced NC NF- kB 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- kB. 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- kB activation, and highlight NIK as a potential therapeutic target in a defined subset of DLBCL. [ABSTRACT FROM AUTHOR]