title: Identification of C/EBPβ target genes in ALK+ anaplastic large cell lymphoma (ALCL) by gene expression profiling and chromatin immunoprecipitation.
abstract: C/EBPβ (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBPβ responsible for ALK-mediated oncogenesis. C/EBPβ was knocked down in ALK+ ALCL cell lines with a C/EBPβ-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBPβ. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBPβ was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBPβ-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBPβ in ALK-mediated oncogenesis.
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital Tübingen and Comprehensive Cancer Center, Eberhard-Karls-University, Tübingen, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Bonzheim
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.forename: Margit
authors.initials: M
authors.lastname: Klier-Richter
authors.forename: Julia
authors.initials: J
authors.lastname: Steinhilber
authors.forename: Nataša
authors.initials: N
authors.lastname: Anastasov
authors.forename: Sabine
authors.initials: S
authors.lastname: Schäfer
authors.forename: Patrick
authors.initials: P
authors.lastname: Adam
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
mesh_terms: D022782:CCAAT-Enhancer-Binding Protein-beta / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015778:Minor Histocompatibility Antigens; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C096816:BCL2-related protein A1; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D018797:Cell Cycle Proteins; C508073:G0S2 protein, human; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C501726:DDX21 protein, human; D053487:DEAD-box RNA Helicases