title: BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-p53 axis in diffuse large B-cell lymphoma.
abstract: The B-aggressive lymphoma-1 protein and ADP-ribosyltransferase BAL1/ARTD9 has been recently identified as a risk-related gene product in aggressive diffuse large B-cell lymphoma (DLBCL). BAL1 is constitutively expressed in a subset of high-risk DLBCLs with an active host inflammatory response and has been suggested to be associated with interferon-related gene expression. Here we identify BAL1 as a novel oncogenic survival factor in DLBCL and show that constitutive overexpression of BAL1 in DLBCL tightly associates with intrinsic interferon-gamma (IFNγ) signaling and constitutive activity of signal transducer and activator of transcription (STAT)-1. Remarkably, BAL1 stimulates the phosphorylation of both STAT1 isoforms, STAT1α and STAT1β, on Y701 and thereby promotes the nuclear accumulation of the antagonistically acting and transcriptionally repressive isoform STAT1β. Moreover, BAL1 physically interacts with both STAT1α and STAT1β through its macrodomains in an ADP-ribosylation-dependent manner. BAL1 directly inhibits, together with STAT1β, the expression of tumor suppressor and interferon response factor (IRF)-1. Conversely, BAL1 enhances the expression of the proto-oncogenes IRF2 and B-cell CLL/lymphoma (BCL)-6 in DLBCL. Our results show for the first time that BAL1 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-p53 axis and mediates proliferation, survival and chemo-resistance in DLBCL. As a consequence constitutive IFNγ-STAT1 signaling does not lead to apoptosis but rather to chemo-resistance in DLBCL overexpressing BAL1. Our results suggest that BAL1 may induce an switch in STAT1 from a tumor suppressor to an oncogene in high-risk DLBCL.
authors.affiliation: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Camicia
authors.forename: Samia B
authors.initials: SB
authors.lastname: Bachmann
authors.forename: Hans C
authors.initials: HC
authors.lastname: Winkler
authors.forename: Marc
authors.initials: M
authors.lastname: Beer
authors.forename: Marianne
authors.initials: M
authors.lastname: Tinguely
authors.forename: Eugenia
authors.initials: E
authors.lastname: Haralambieva
authors.forename: Paul O
authors.initials: PO
authors.lastname: Hassa
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D050836:Interferon Regulatory Factor-2 / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C573415:IFNG protein, human; C494257:IRF1 protein, human; C494229:IRF2 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D009363:Neoplasm Proteins; C418133:PARP9 protein, human; D020033:Protein Isoforms; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma; D011065:Poly(ADP-ribose) Polymerases
keywords: ADP-ribosylation; BAL1/ARTD9; Diffuse large B-cell lymphoma; IFNγ-STAT1-signaling; IRF1; Macrodomains; Survival; p53