Identification of C/EBPβ target genes in ALK+ anaplastic large cell lymphoma (ALCL) by gene expression profiling and chromatin immunoprecipitation

PLoS One. 2013 May 31;8(5):e64544. doi: 10.1371/journal.pone.0064544. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CCAAT-Enhancer-Binding Protein-beta / antagonists & inhibitors
  • CCAAT-Enhancer-Binding Protein-beta / genetics*
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Chromatin Immunoprecipitation
  • DEAD-box RNA Helicases / genetics*
  • DEAD-box RNA Helicases / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Lymphoma, Large-Cell, Anaplastic / metabolism
  • Lymphoma, Large-Cell, Anaplastic / pathology
  • Minor Histocompatibility Antigens
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Transcription, Genetic

Substances

  • BCL2-related protein A1
  • CCAAT-Enhancer-Binding Protein-beta
  • CEBPB protein, human
  • Cell Cycle Proteins
  • G0S2 protein, human
  • Minor Histocompatibility Antigens
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • DDX21 protein, human
  • DEAD-box RNA Helicases

Grant support

This work was supported by the SFB 685 “Immunotherapy” of the University of Tübingen, TP B8 (LQM and FF) and by the IZKF fortüne program, University of Tübingen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.