Ballestar, E. (E.)

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    Epigenetic Signatures Associated with Different Levels of Differentiation Potential in Human Stem Cells
    (Public Library of Science, 2009) Cigudosa, J.C. (Juan Cruz); Roman-Gomez, J. (José); Ballestar, E. (E.); Aranda, P. (P.); Prieto, I. (Inés); Andreu, E.J. (Enrique José); Siebert, R. (Reiner); Esteller, M. (Manel); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio)
    The therapeutic use of multipotent stem cells depends on their differentiation potential, which has been shown to be variable for different populations. These differences are likely to be the result of key changes in their epigenetic profiles.
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    Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction
    (2021) Álvarez-Prado, A.F. (Ángel F.); Durandy, A. (Anne); Vilas, A. (Amaia); Català-Moll, F. (Francesc); Colobran, R. (Roger); Hammarstrom, L. (Lennart); Ballestar, E. (E.); Abolhassani, H. (Hassan); Martínez-Gallo, M. (Mónica); Ferreté-Bonastre, A.G. (Anna G.); Li, T. (Tianlu); Lutsik, P. (Pavlo); Martín-Nalda, A. (Andrea); Klemann, C. (Christian); Ciudad, L. (Laura); Rivière, J.G. (Jacques); Grimbacher, B. (Bodo); Plass, C. (Christoph); Prosper-Cardoso, F. (Felipe); Kracker, S. (Sven); Weichenhan, D. (Dieter); Rodríguez-Ubreva, J. (Javier); Dieli-Crimi, R. (Romina); Speckmann, C. (Carsten); Soler-Palacín, P. (Pere)
    Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naive and memory B cells both display widespread DNA methylation alterations, of which similar to 25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis indicates that AID is not directly involved. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naive B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.
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    BCR-ABL1-induced expression of HSPA8 promotes cell survival in chronic myeloid leukaemia
    (Wiley-Blackwell, 2008) Isidro, I. (Isabel); Cordeu, L. (Lucía); Jimenez-Velasco, A. (A.); Roman-Gomez, J. (José); San-Jose-Eneriz, E. (Edurne); Heiniger, A. (A.); Garate, L. (Leire); Ballestar, E. (E.); Andreu, E.J. (Enrique José); Gutierrez, N.C. (Norma C.); Guruceaga, E. (Elizabeth); Esteller, M. (Manel); Prosper-Cardoso, F. (Felipe); Torres, A. (Antonio); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier); Rubio, A. (Ángel); Perez-Roger, I. (Ignacio)
    In order to determine new signal transduction pathways implicated in chronic myeloid leukaemia (CML), we performed a gene expression profile comparison between CD34+ cells from CML patients and healthy donors. Functional studies were performed using the Mo7e and Mo7e-p210 cell lines. Expression of CCND1 (Cyclin D1), as well as the chaperone HSPA8, which is important for regulation of CCND1, were significantly upregulated in CD34+ CML cells. Upregulation of HSPA8 was dependent, at least in part, on STAT5 (signal transducer and activator of transcrition 5)-dependent transcriptional activation, as demonstrated by chromatin immunoprecipitation. The presence of HSPA8 in the nuclear protein fraction as well as its binding to CCND1 suggests that it may contribute to stabilization of the CCND1/CDK4 complex, which, in turn, may participate in proliferation of CML cells. Treatment of CML cells with the specific HSPA8 inhibitor 15-deoxyspergualin induced inhibition of CML cell viability but did not induce apoptosis. In conclusion, our studies suggest that STAT5-mediated activation of HSPA8 induces nuclear translocation and activation of the CCND1/CDK4 complex leading to increased proliferation of CML cells, deciphering a new pathway implicated in CML and supporting a potential role of chaperone inhibitors in the treatment of CML.
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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.