Ott, G. (German)

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    Epigenetic activation of SOX11 in lymphoid neoplasms by histone modifications
    (Public Library of Science, 2011) Jares, P. (Pedro); Salaverria-Lete, I. (Itziar); Richter, J. (Julia); Roman-Gomez, J. (José); Xargay-Torrent, S. (Silvia); Rosenwald, A. (Andreas); Ott, G. (German); Enjuanes, A. (Anna); Bea, S. (Silvia); Palomero, J. (Jara); Royo, C. (Cristina); Martin-Guerrero, I. (Idoia); Hernandez, L. (Luis); Amador, V. (Virginia); Campo, E. (Elías); Siebert, R. (Reiner); Balint, B. (Balazs); Lujambio, A. (Amaya); Esteller, M. (Manel); Vegliante, M.C. (Maria Carmela); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio)
    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
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    New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling
    (American Society of Hematology, 2009) Stürzenhofecker, B. (Benjamin); Cogliatti, S. (S.B.); Stein, H. (Harald); Ammerpohl, O. (Ole); Hasenclever, D. (D.); Richter, J. (Julia); Korn, B. (Bernhard); Trümper, L. (Lorenz); Kreuz, M. (Markus); Berger, H. (H.); Rosenwald, A. (Andreas); Drexler, H.G. (Hans G.); Ott, G. (German); Loeffler, M. (Markus); Weber, M. (Michael); Schübeler, D. (Dirk); Bentink, S. (S.); Ballestar, E. (E.); Fraga, M.F. (Mario F.); Bernd, H.W (H.W.); Seifert, M. (Marc); Möller, P. (Peter); Bibikova, M. (Marina); Küppers, R. (Ralf); Klapper, W. (Wolfram); Siebert, R. (Reiner); Barker, D. (D.); Esteller, M. (Manel); Wessendorf, S. (Swen); Wickham, E. (Eliza); Hummel, M. (M.); Rosolowski, M. (Maciej); Schwaenen, C. (Carsten); Hansmann, M.L. (Martin-Leo); Potter, K. (Kathleen N.); Prosper-Cardoso, F. (Felipe); Spang, R. (Rainer); Fan, J.B. (Jian-Bing); Calvanese, V. (V.); Lopez-Serra, L. (Lidia); MacLeod, R.A.F. (Roderick A.F.); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio)
    Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic, and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) characterized for their morphologic, genetic, and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchic clustering indicated that methylation patterns in maB-NHLs were not strictly associated with morphologic, genetic, or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype–specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHLs studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in nonhematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHLs with different morphologic, genetic, and transcriptional background share a similar stem cell–like epigenetic pattern. This suggests that maB-NHLs originate from cells with stem cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling.