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

Item Type:Article
Title:IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL
Creators Name:Nogai, H. and Wenzel, S.S. and Hailfinger, S. and Grau, M. and Kaergel, E. and Seitz, V. and Wollert-Wulf, B. and Pfeifer, M. and Wolf, A. and Frick, M. and Dietze, K. and Madle, H. and Tzankov, A. and Hummel, M. and Dörken, B. and Scheidereit, C. and Janz, M. and Lenz, P. and Thome, M. and Lenz, G.
Abstract:Constitutive activation of the nuclear factor-κ B (NF-κB) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-κB 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 IκB protein IκB-ζ to be upregulated in ABC compared to germinal center B-cell-like (GCB) DLBCL primary patient samples. Knockdown of IκB-ζ by RNA interference was toxic to ABC but not GCB DLBCL cell lines. Gene expression profiling following IκB-ζ knockdown demonstrated a significant downregulation of a large number of known NF-κB target genes, indicating an essential role of IκB-ζ in regulating a specific set of NF-κB target genes. To further investigate how IκB-ζ mediates NF-κB activity, we performed immunoprecipitations and detected a physical interaction of IκB-ζ with both p50 and p52 NF-κB subunits, indicating that IκB-ζ interacts with components of both the canonical and the non-canonical NF-κB pathway in ABC DLBCL. Collectively, our data demonstrate that IκB-ζ is essential for nuclear NF-κB activity in ABC DLBCL and thus might represent a promising molecular target for future therapies.
Keywords:Diffuse Large B-Cell Lymphoma, Enzyme-Linked Immunosorbent Assay, Gene Knockdown Techniques, Gene Regulatory Networks, Genetic Transduction, Immunoprecipitation, NF-κB, Nuclear Proteins, Polymerase Chain Reaction, Signal Transduction, Small Interfering RNA, Transcriptome, Western Blotting
Publisher:American Society of Hematology
Page Range:2242-2250
Date:26 September 2013
Official Publication:https://doi.org/10.1182/blood-2013-06-508028
PubMed:View item in PubMed

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