IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL

Constitutive activation of the nuclear factor-kappa B (NF-kappa B) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-kappa B regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the atypical nuclear I kappa B protein I kappa B-zeta to be upregulated in ABC compared with germinal center B-cell-like (GCB) DLBCL primary patient samples. Knockdown of I kappa B-zeta by RNA interference was toxic to ABC but not to GCB DLBCL cell lines. Gene expression profiling after I kappa B-zeta knockdown demonstrated a significant downregulation of a large number of known NF-kappa B target genes, indicating an essential role of I kappa B-zeta in regulating a specific set of NF-kappa B target genes. To further investigate how I kappa B-zeta mediates NF-kappa B activity, we performed immunoprecipitations and detected a physical interaction of I kappa B-zeta with both p50 and p52 NF-kappa B subunits, indicating that I kappa B-zeta interacts with components of both the canonical and the noncanonical NF-kappa B pathway in ABC DLBCL. Collectively, our data demonstrate that I kappa B-zeta is essential for nuclear NF-kappa B activity in ABC DLBCL, and thus might represent a promising molecular target for future therapies.