TRAF3 loss- of- function reveals the noncanonical NF-K 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 -K B 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 -K B kinase, and increased NC NF -K B pathway activity. Accordingly, TRAF3 genetic ablation in isogenic DLBCL model systems caused upregulation of NIK and enhanced NC NF -K B 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 -K B. 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) gamma , which were restored following neutralization of IL - 10. Our findings corroborate a direct relationship between TRAF3 genetic alterations and NC NF -K B activation, and highlight NIK as a potential therapeutic target in a defined subset of DLBCL.