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| Item Type: | Article |
|---|---|
| Title: | Inactivation of the putative ubiquitin-E3 ligase PDLIM2 in classical Hodgkin and anaplastic large cell lymphoma |
| Creators Name: | Wurster, K.D. and Hummel, F. and Richter, J. and Giefing, M. and Hartmann, S. and Hansmann, M.L. and Kreher, S. and Köchert, K. and Krappmann, D. and Klapper, W. and Hummel, M. and Wenzel, S.S. and Lenz, G. and Janz, M. and Dörken, B. and Siebert, R. and Mathas, S. |
| Abstract: | Apart from its unique histopathological appearance with rare tumor cells embedded in an inflammatory background of bystander cells, classical Hodgkin lymphoma (cHL) is characterized by an unusual activation of a broad range of signaling pathways involved in cellular activation. This includes constitutive high-level activity of NF-{kappa}B, JAK/STAT, AP-1 and IRF transcription factors (TFs), which are physiologically only transiently activated. Here, we demonstrate that inactivation of the putative ubiquitin E3-ligase PDLIM2 contributes to this TF activation. PDLIM2 expression is lost at the mRNA and protein level in the majority of cHL cell lines and HRS cells of nearly all cHL primary samples. This loss is associated with PDLIM2 genomic alterations, promoter methylation and altered splicing. Reconstitution of PDLIM2 in HRS cell lines inhibits proliferation, blocks NF-{kappa}B transcriptional activity and contributes to cHL-specific gene expression. In non-Hodgkin B cell lines, siRNA-mediated PDLIM2 knockdown results in super-activation of TFs NF-{kappa}B and AP-1 following PMA stimulation. Furthermore, expression of PDLIM2 is lost in anaplastic large cell lymphoma (ALCL), which shares key biological aspects with cHL. We conclude that inactivation of PDLIM2 is a recurrent finding in cHL and ALCL, promotes activation of inflammatory signaling pathways and thereby contributes to their pathogenesis. |
| Keywords: | Anaplastic Large-Cell Lymphoma, Base Sequence, Cluster Analysis, DNA Methylation, Enzyme Activation, Gene Silencing, Genetic Loci, Genetic Promoter Regions, Hodgkin Disease, LIM Domain Proteins, Microfilament Proteins, Mutation, NF-kappa B, Neoplastic Gene Expression Regulation, Proteolysis, RNA Splice Sites, Transcription Factors, Tumor Cell Line, Ubiquitin-Protein Ligases |
| Source: | Leukemia |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Volume: | 31 |
| Number: | 3 |
| Page Range: | 602-613 |
| Date: | March 2017 |
| Official Publication: | https://doi.org/10.1038/leu.2016.238 |
| PubMed: | View item in PubMed |
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