title: CARMA1- and MyD88-dependent activation of Jun/ATF-type AP-1 complexes is a hallmark of ABC diffuse large B-cell lymphomas.
abstract: A hallmark of the diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) type, a molecular subtype characterized by adverse outcome, is constitutive activation of the transcription factor nuclear factor-κB (NF-κB), which controls expression of genes promoting cellular survival and proliferation. Much less, however, is known about the role of the transcription factor activator protein-1 (AP-1) in ABC DLBCL. Here, we show that AP-1, like NF-κB, was controlled by constitutive activation of the B-cell receptor signaling component caspase recruitment domain-containing membrane-associated guanylate kinase 1 (CARMA1) and/or the Toll-like receptor signaling component myeloid differentiation primary response gene 88 (MyD88) in ABC DLBCL cell lines. In contrast to germinal center (GC) B-cell (GCB) DLBCL, ABC DLBCL cell lines expressed high levels of the AP-1 family members c-Jun, JunB, and JunD, which formed heterodimeric complexes with the AP-1 family members activating transcription factor (ATF) 2, ATF3, and ATF7. Inhibition of these complexes by a dominant-negative approach led to impaired growth of a majority of ABC DLBCL cell lines. Individual silencing of c-Jun, ATF2, or ATF3 decreased cellular survival and revealed c-Jun/ATF2-dependent control of ATF3 expression. As a consequence, ATF3 expression was much higher in ABC vs GCB DLBCL cell lines. Samples derived from DLBCL patients showed a clear trend toward high and nuclear ATF3 expression in nodal DLBCL of the non-GC or ABC subtype. These findings identify the activation of AP-1 complexes of the Jun/ATF-type as an important element controlling the growth of ABC DLBCL.
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland;
authors.forename: Mélanie
authors.initials: M
authors.lastname: Juilland
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland;
authors.forename: Montserrat
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: Translational Oncology, Department of Medicine A, University Hospital Münster, Münster, Germany; Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany;
authors.forename: Tabea
authors.initials: T
authors.lastname: Erdmann
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland;
authors.forename: Yara
authors.initials: Y
authors.lastname: Banz
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland;
authors.forename: Zala
authors.initials: Z
authors.lastname: Jevnikar
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland;
authors.forename: Stephan
authors.initials: S
authors.lastname: Hailfinger
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland;
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Department of Physics, Philipps-University Marburg, Marburg, Germany; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Grau
authors.affiliation: Translational Oncology, Department of Medicine A, University Hospital Münster, Münster, Germany; Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.affiliation: Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Urban
authors.initials: U
authors.lastname: Novak
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland;
authors.forename: Margot
authors.initials: M
authors.lastname: Thome
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D051696:Activating Transcription Factors / Q000235:genetics / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C497105:ATF2 protein, human; C490449:ATF3 protein, human; C427752:ATF7 protein, human; D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; D051696:Activating Transcription Factors; D053468:CARD Signaling Adaptor Proteins; C581727:JunB protein, human; C559371:JunD protein, human; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C426242:CARD11 protein, human; D006162:Guanylate Cyclase