Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-14063 Wissenschaftlicher Artikel Enjuanes, Anna; Fernandez, Veronica; Hernandez, Luis; Navarro, Alba; Bea, Silvia; Pinyol, Magda; Lopez-Guillermo, Armando; Rosenwald, Andreas; Ott, German; Campo, Elias; Jares, Pedro Identification of Methylated Genes Associated with Aggressive Clinicopathological Features in Mantle Cell Lymphoma Background: Mantle cell lymphoma (MCL) is genetically characterized by the t(11; 14)(q13; q32) translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance. Methodology/Principal Findings: To identify potential methylated genes in MCL we initially investigated seven MCL cell lines treated with epigenetic drugs and gene expression microarray profiling. The methylation status of selected candidate genes was validated by a quantitative assay and subsequently analyzed in a series of primary MCL (n = 38). After pharmacological reversion we identified 252 potentially methylated genes. The methylation analysis of a subset of these genes (n = 25) in the MCL cell lines and normal B lymphocytes confirmed that 80% of them were methylated in the cell lines but not in normal lymphocytes. The subsequent analysis in primary MCL identified five genes (SOX9, HOXA9, AHR, NR2F2, and ROBO1) frequently methylated in these tumours. The gene methylation events tended to occur in the same primary neoplasms and correlated with higher proliferation, increased number of chromosomal abnormalities, and shorter survival of the patients. Conclusions: We have identified a set of genes whose methylation degree and gene expression levels correlate with aggressive clinicopathological features of MCL. Our findings also suggest that a subset of MCL might show a CpG island methylator phenotype (CIMP) that may influence the behaviour of the tumours. 2011 e19736 PLoS ONE 6 5 urn:nbn:de:bvb:20-opus-140632 10.1371/journal.pone.0019736 Pathologisches Institut OPUS4-13532 Wissenschaftlicher Artikel Carmela Vegliante, Maria; Royo, Cristina; Palomero, Jara; Salaverria, Itziar; Balint, Balazs; Martin-Guerrero, Idoia; Agirre, Xabier; Lujambio, Amaia; Richter, Julia; Xargay-Torrent, Silvia; Bea, Silvia; Hernandez, Luis; Enjuanes, Anna; Jose Calasanz, Maria; Rosenwald, Andreas; Ott, German; Roman-Gomez, Jose; Prosper, Felipe; Esteller, Manel; Jares, Pedro; Siebert, Reiner; Campo, Elias; Martin-Subero, Jose I.; Amador, Virginia Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications. 2011 e21382 PLoS ONE 6 6 urn:nbn:de:bvb:20-opus-135325 10.1371/journal.pone.0021382 Pathologisches Institut