I{kappa}B-{zeta} controls the constitutive NF-{kappa}B 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 to 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 GCB DLBCL cell lines. Gene expression profiling following I{kappa}B-{zeata} 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 non-canonical 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.