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

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Item Type:	Article
Title:	IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL
Creators Name:	Nogai, H., Wenzel, S.S., Hailfinger, S., Grau, M., Kaergel, E., Seitz, V., Wollert-Wulf, B., Pfeifer, M., Wolf, A., Frick, M., Dietze, K., Madle, H., Tzankov, A., Hummel, M., Dörken, B., Scheidereit, C., Janz, M., Lenz, P., 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
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	122
Number:	13
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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