title: IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL.
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 with germinal center B-cell-like (GCB) DLBCL primary patient samples. Knockdown of IκB-ζ by RNA interference was toxic to ABC but not to GCB DLBCL cell lines. Gene expression profiling after 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 noncanonical 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.
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Molecular Cancer Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Hendrik
authors.initials: H
authors.lastname: Nogai
authors.forename: Sören-Sebastian
authors.initials: SS
authors.lastname: Wenzel
authors.forename: Stephan
authors.initials: S
authors.lastname: Hailfinger
authors.forename: Michael
authors.initials: M
authors.lastname: Grau
authors.forename: Eva
authors.initials: E
authors.lastname: Kaergel
authors.forename: Volkhard
authors.initials: V
authors.lastname: Seitz
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wollert-Wulf
authors.forename: Matthias
authors.initials: M
authors.lastname: Pfeifer
authors.forename: Annette
authors.initials: A
authors.lastname: Wolf
authors.forename: Mareike
authors.initials: M
authors.lastname: Frick
authors.forename: Kerstin
authors.initials: K
authors.lastname: Dietze
authors.forename: Hannelore
authors.initials: H
authors.lastname: Madle
authors.forename: Alexander
authors.initials: A
authors.lastname: Tzankov
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Claus
authors.initials: C
authors.lastname: Scheidereit
authors.forename: Martin
authors.initials: M
authors.lastname: Janz
authors.forename: Peter
authors.initials: P
authors.lastname: Lenz
authors.forename: Margot
authors.initials: M
authors.lastname: Thome
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006801:Humans; D020672:I-kappa B Proteins; D047468:Immunoprecipitation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D059467:Transcriptome; D014161:Transduction, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; D016328:NF-kappa B; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering