PuSH - Publication Server of Helmholtz Zentrum München: Identification of C/EBPβ target genes in ALK+ Anaplastic Large Cell Lymphoma (ALCL) by gene expression profiling and chromatin immunoprecipitation.

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Bonzheim, I. ; Irmler, M. ; Klier-Richter, M. ; Steinhilber, J.* ; Anastasov, N. ; Schafer, S.* ; Adam, P.* ; Beckers, J. ; Raffeld, M.* ; Fend, F.* ; Quintanilla-Martinez, L.

Identification of C/EBPβ target genes in ALK+ Anaplastic Large Cell Lymphoma (ALCL) by gene expression profiling and chromatin immunoprecipitation.

PLoS ONE 8:e64544 (2013)

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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.

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