35 results on '"Duran-Ferrer M"'
Search Results
2. Analysis of the spatial variation of Bovine tuberculosis disease risk in Spain (2006–2009)
- Author
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Allepuz, A., Casal, J., Napp, S., Saez, M., Alba, A., Vilar, M., Domingo, M., González, M.A., Duran-Ferrer, M., Vicente, J., Álvarez, J., Muñoz, M., and Saez, J.L.
- Published
- 2011
- Full Text
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3. A SIMPLE EPIGENETIC SIGNATURE DEFINES TWO BIOLOGIC GROUPS OF MANTLE CELL LYMPHOMA
- Author
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Bühler, M. M., primary, Kulis, M., additional, Duran‐Ferrer, M., additional, Clot, G., additional, Nadeu, F., additional, Navarro, A., additional, López, C., additional, Giné, E., additional, Beà, S., additional, Campo, E., additional, and Martín‐Subero, J. I., additional
- Published
- 2021
- Full Text
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4. Chronic lymphocytic leukemias with trisomy 12 show a distinct DNA methylation profile linked to altered chromatin activation
- Author
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Tsagiopoulou, M. Chapaprieta, V. Duran-Ferrer, M. Moysiadi, T. Psomopoulos, F. Kollia, P. Papakonstantinou, N. Campo, E. Stamatopoulos, K. Martin-Subero, J.I.
- Published
- 2020
5. DNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy
- Author
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Tsagiopoulou, M. Papakonstantinou, N. Moysiadis, T. Mansouri, L. Ljungström, V. Duran-Ferrer, M. Malousi, A. Queirós, A.C. Plevova, K. Bhoi, S. Kollia, P. Oscier, D. Anagnostopoulos, A. Trentin, L. Ritgen, M. Pospisilova, S. Stavroyianni, N. Ghia, P. Martin-Subero, J.I. Pott, C. Rosenquist, R. Stamatopoulos, K.
- Subjects
hemic and lymphatic diseases - Abstract
Background: In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen. Results: The extent of identified changes in CLL cells versus memory B cells from healthy donors was termed "epigenetic burden" (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed "relapse changes" (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology. Conclusions: Overall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features. © 2019 The Author(s).
- Published
- 2019
6. Antibody response and antigen-specific gamma-interferon profiles of vaccinated and unvaccinated pregnant sheep experimentally infected with Brucella melitensis
- Author
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Durán-Ferrer, M, Léon, L, Nielsen, K, Caporale, V, Mendoza, J, Osuna, A, Perales, A, Smith, P, De-Frutos, C, Gómez-Martı́n, B, Lucas, A, Chico, R, Delgado, O.D, Escabias, J.C, Arrogante, L, Dı́az-Parra, R, and Garrido, F
- Published
- 2004
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7. S843 THE PROLIFERATIVE HISTORY SHAPES THE DNA METHYLOME OF B-CELL TUMORS AND PREDICTS CLINICAL OUTCOME
- Author
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Duran-Ferrer, M., primary, Clot, G., additional, Nadeu, F., additional, Beekman, R., additional, Baumann, T., additional, Nordlund, J., additional, Marincevic-Zuniga, Y., additional, Rivas-Delgado, A., additional, Ordoñez, R., additional, Castellano, G., additional, Kulis, M., additional, Queirós, A., additional, Seung-Tae, L., additional, Wiemels, J., additional, Royo, R., additional, Puiggrós, M., additional, Torrents, D., additional, Giné, E., additional, Beà, S., additional, Jares, P., additional, Agirre, X., additional, Prosper, F., additional, López-Otín, C., additional, Puente, X.S., additional, Delgado, J., additional, López-Guillermo, A., additional, Campo, E., additional, and Martín-Subero, J.I., additional
- Published
- 2019
- Full Text
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8. PF567 CHROMATIN ACTIVATION AS A UNIFYING PRINCIPLE UNDERLYING PATHOGENIC MECHANISMS IN MULTIPLE MYELOMA
- Author
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Ordoñez, R., primary, Kulis, M., additional, Russiñol, N., additional, Chapaprieta, V., additional, Beekman, R., additional, Meydan, C., additional, Duran-Ferrer, M., additional, Verdaguer-Dot, N., additional, Clot, G., additional, Vilarrasa-Blasi, R., additional, Garate, L., additional, Miranda, E., additional, Carrasco, A., additional, Ezponda, T., additional, Martens, J.H.A., additional, El-Omri, H., additional, Taha, R.Y., additional, Calasanz, M.J., additional, Paiva, B., additional, Miguel, J. San, additional, Flicek, P., additional, Gut, I., additional, Melnick, A., additional, Mitsiades, C.S., additional, Licht, J.D., additional, Campo, E., additional, Stunnenberg, H.G., additional, Agirre, X., additional, Martin-Subero, J.I., additional, and Prósper, F., additional
- Published
- 2019
- Full Text
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9. Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage
- Author
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Queiros, A.C., Beekman, R., Vilarrasa-Blasi, R., Duran-Ferrer, M., Clot, G., Merkel, A., Raineri, E., Russinol, N., Castellano, G., Bea, S., Navarro, A., Kulis, M., Verdaguer-Dot, N., Jares, P., Enjuanes, A., Calasanz, M.J., Bergmann, A., Vater, I., Salaverria, I., van de Werken, H.J., Wilson, W.H., Datta, A., Flicek, P., Royo, R., Martens, J.H.A., Gine, E., Lopez-Guillermo, A., Stunnenberg, H., Klapper, W., Pott, C., Heath, S., Gut, I.G., Siebert, R., Campo, E., Martin-Subero, J.I., Queiros, A.C., Beekman, R., Vilarrasa-Blasi, R., Duran-Ferrer, M., Clot, G., Merkel, A., Raineri, E., Russinol, N., Castellano, G., Bea, S., Navarro, A., Kulis, M., Verdaguer-Dot, N., Jares, P., Enjuanes, A., Calasanz, M.J., Bergmann, A., Vater, I., Salaverria, I., van de Werken, H.J., Wilson, W.H., Datta, A., Flicek, P., Royo, R., Martens, J.H.A., Gine, E., Lopez-Guillermo, A., Stunnenberg, H., Klapper, W., Pott, C., Heath, S., Gut, I.G., Siebert, R., Campo, E., and Martin-Subero, J.I.
- Abstract
Contains fulltext : 161703.pdf (publisher's version ) (Open Access)
- Published
- 2016
10. Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage
- Author
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Queiros, A C, Beekman, R, Vilarrasa-Blasi, R, Duran-Ferrer, M, Clot, G, Merkel, A, Raineri, E, Russinol, N, Castellano, G, Bea, S, Navarro, A, Kulis, M, Verdaguer-Dot, N, Jares, P, Enjuanes, A, Calasanz, MJ, Bergmann, A, Vater, I, Salaverria, I, van de Werken, Harmen, Wilson, WH, Datta, A, Flicek, P, Royo, R, Martens, J, Gine, E, Lopez-Guillermo, A, Stunnenberg, HG, Klapper, W, Pott, C, Heath, S, Gut, I G, Siebert, R, Campo, E, Martin-Subero, JI, Queiros, A C, Beekman, R, Vilarrasa-Blasi, R, Duran-Ferrer, M, Clot, G, Merkel, A, Raineri, E, Russinol, N, Castellano, G, Bea, S, Navarro, A, Kulis, M, Verdaguer-Dot, N, Jares, P, Enjuanes, A, Calasanz, MJ, Bergmann, A, Vater, I, Salaverria, I, van de Werken, Harmen, Wilson, WH, Datta, A, Flicek, P, Royo, R, Martens, J, Gine, E, Lopez-Guillermo, A, Stunnenberg, HG, Klapper, W, Pott, C, Heath, S, Gut, I G, Siebert, R, Campo, E, and Martin-Subero, JI
- Published
- 2016
11. Whole-genome fingerprint of the DNA methylome during human B cell differentiation
- Author
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Kulis, M., Merkel, A., Heath, S., Queiros, A.C., Schuyler, R.P., Castellano, G., Beekman, R., Raineri, E., Esteve, A., Clot, G., Verdaguer-Dot, N., Duran-Ferrer, M., Russinol, N., Vilarrasa-Blasi, R., Ecker, S., Pancaldi, V., Rico, D., Agueda, L., Blanc, J., Richardson, D., Clarke, L., Datta, A., Pascual, M., Agirre, X., Prosper, F., Alignani, D., Paiva, B., Caron, G., Fest, T., Muench, M.O., Fomin, M.E., Lee, S.T., Wiemels, J.L., Valencia, A., Gut, M., Flicek, P., Stunnenberg, H.G., Siebert, R., Kuppers, R., Gut, I.G., Campo, E., Martin-Subero, J.I., Kulis, M., Merkel, A., Heath, S., Queiros, A.C., Schuyler, R.P., Castellano, G., Beekman, R., Raineri, E., Esteve, A., Clot, G., Verdaguer-Dot, N., Duran-Ferrer, M., Russinol, N., Vilarrasa-Blasi, R., Ecker, S., Pancaldi, V., Rico, D., Agueda, L., Blanc, J., Richardson, D., Clarke, L., Datta, A., Pascual, M., Agirre, X., Prosper, F., Alignani, D., Paiva, B., Caron, G., Fest, T., Muench, M.O., Fomin, M.E., Lee, S.T., Wiemels, J.L., Valencia, A., Gut, M., Flicek, P., Stunnenberg, H.G., Siebert, R., Kuppers, R., Gut, I.G., Campo, E., and Martin-Subero, J.I.
- Abstract
Contains fulltext : 144901.pdf (Publisher’s version ) (Closed access)
- Published
- 2015
12. Complementary tools for the control and eradication of caprine and ovine brucellosis in the European Union
- Author
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CRESPO LEON, F., primary, SAEZ LLORENTE, J.L., additional, RIVIRIEGO GORDEJO, F.J., additional, RODRIGUEZ FERRI, E.F., additional, and DURAN FERRER, M, additional
- Published
- 2012
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13. Comparison of serological tests for the detection of ovine and caprine antibody to Brucella melitensis
- Author
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NIELSEN, K., primary, GALL, D., additional, SMITH, P.G., additional, BALSEVICIUS, S., additional, GARRIDO ABELLAN, F., additional, DURAN FERRER, M, additional, BIANCIFIORI, F., additional, DAJER, A., additional, LUNA, E., additional, SAMARTINO, L.E., additional, BERMUDEZ, R., additional, MORENO, F., additional, RENTERIA, T., additional, and CORRAL, A., additional
- Published
- 2004
- Full Text
- View/download PDF
14. The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome
- Author
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Duran-Ferrer, M. (Martí)
- Subjects
- Chronic lymphocytic-leukemia, Multiple-myeloma, Molecular classification, Methylation landscape, Lymphoma, Expression, Genes, Hypermethylation, Differentiation, Hypomethylation
- Abstract
We report a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. Differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive individual-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. We construct a DNA-methylation-based mitotic clock, called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in differential diagnosis and the prediction of clinical outcome. Martin-Subero and colleagues analyze DNA methylation patterns in B-cell tumors and their normal cells of origin, and develop epiCMIT, a methylation-based mitotic clock with prognostic relevance.
- Published
- 2020
15. INTEGRATIVE ANALYSIS OF THE GENOME, EPIGENOME, TRANSCRIPTOME AND THREE-DIMENSIONAL CHROMATIN STRUCTURE IN CHRONIC LYMPHOCYTIC LEUKEMIA
- Author
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Beekman, R., Russinol, N., Chapaprieta, V., Verdaguer-Dot, N., Vilarrasa-Blasi, R., Clot, G., Duran-Ferrer, M., Kulis, M., Castellano, G., Javierre, B. M., Wingett, S. W., Blanc, J., Serra, F., Merkel, A., Ullrich, S., Vlasova, A., Palumbo, E., Pinyol, M., Sílvia Beà, Royo, R., Puiggros, M., Datta, A., Flicek, P., Lowy, E., Kostadima, M., Clarke, L., Delgado, J., Lopez-Guillermo, A., Puente, X. S., Lopez-Otin, C., Torrents, D., Yaspo, M-L, Aymerich, M., Heath, S., Guigo, R., Gut, M., Fraser, P., Marti-Renom, M., Gut, I., Martens, J., Stunnenberg, H., Campo, E., and Martin-Subero, I.
16. DECODING THE ENTIRE DNA METHYLOME OF MANTLE CELL LYMPHOMA: NEW BIOLOGICAL AND CLINICAL INSIGHTS
- Author
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Beekman, R., Queiros, A. C., Vilarrasa-Blasi, R., Merkel, A., Raineri, E., Castellano, G., Bea, S., Navarro, A., Russinol, N., Clot, G., Kulis, M., Duran-Ferrer, M., Jares, P., Enjuanes, A., MJ Calasanz, Bergmann, A., Vater, I., Salaverria, I., Werken, H. J. G., Wilson, W. H., Datta, A., Flicek, P., Martens, J., Gine, E., Lopez-Guillermo, A., Stunnenberg, H. G., Klapper, W., Pott, C., Heath, S., Gut, I. G., Siebert, R., Campo, E., and Martin-Subero, J. I.
17. BCL3 rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases.
- Author
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Carbo-Meix A, Guijarro F, Wang L, Grau M, Royo R, Frigola G, Playa-Albinyana H, Buhler MM, Clot G, Duran-Ferrer M, Lu J, Granada I, Baptista MJ, Navarro JT, Espinet B, Puiggros A, Tapia G, Bandiera L, De Canal G, Bonoldi E, Climent F, Ribera-Cortada I, Fernandez-Caballero M, De la Banda E, Do Nascimento J, Pineda A, Vela D, Rozman M, Aymerich M, Syrykh C, Brousset P, Perera M, Yanez L, Ortin JX, Tuset E, Zenz T, Cook JR, Swerdlow SH, Martin-Subero JI, Colomer D, Matutes E, Bea S, Costa D, Nadeu F, and Campo E
- Subjects
- Humans, In Situ Hybridization, Fluorescence, Translocation, Genetic, Gene Rearrangement, Immunoglobulin Heavy Chains genetics, Chromosomes, Human, Pair 14 genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively.
- Published
- 2024
- Full Text
- View/download PDF
18. Robust identification of conventional and leukemic nonnodal mantle cell lymphomas using epigenetic biomarkers.
- Author
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Bühler MM, Kulis M, Duran-Ferrer M, López C, Clot G, Nadeu F, Romo M, Giné E, López-Guillermo A, Beà S, Campo E, and Martín-Subero JI
- Abstract
Competing Interests: The authors declare no conflict of interest.
- Published
- 2024
- Full Text
- View/download PDF
19. Epigenomic Characterization of Lymphoid Neoplasms.
- Author
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Duran-Ferrer M and Martín-Subero JI
- Subjects
- Humans, Chromatin, Epigenesis, Genetic, Mutation, Epigenomics, Lymphoma
- Abstract
Lymphoid neoplasms represent a heterogeneous group of disease entities and subtypes with markedly different molecular and clinical features. Beyond genetic alterations, lymphoid tumors also show widespread epigenomic changes. These severely affect the levels and distribution of DNA methylation, histone modifications, chromatin accessibility, and three-dimensional genome interactions. DNA methylation stands out as a tracer of cell identity and memory, as B cell neoplasms show epigenetic imprints of their cellular origin and proliferative history, which can be quantified by an epigenetic mitotic clock. Chromatin-associated marks are informative to uncover altered regulatory regions and transcription factor networks contributing to the development of distinct lymphoid tumors. Tumor-intrinsic epigenetic and genetic aberrations cooperate and interact with microenvironmental cells to shape the transcriptome at different phases of lymphoma evolution, and intraclonal heterogeneity can now be characterized by single-cell profiling. Finally, epigenetics offers multiple clinical applications, including powerful diagnostic and prognostic biomarkers as well as therapeutic targets.
- Published
- 2024
- Full Text
- View/download PDF
20. IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia.
- Author
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Syrykh C, Pons-Brun B, Russiñol N, Playa-Albinyana H, Baumann T, Duran-Ferrer M, Kulis M, Carbó-Meix A, Mozas P, Alcoceba M, González M, Navarro-Bailón A, Colado E, Payer ÁR, Aymerich M, Terol MJ, Lu J, Knisbacher BA, Hahn CK, Ruiz-Gaspà S, Enjuanes A, Wu CJ, Getz G, Zenz T, López-Guillermo A, Martín-Subero JI, Colomer D, Delgado J, Campo E, and Nadeu F
- Subjects
- Humans, Prognosis, Mutation, Immunoglobulin Heavy Chains genetics, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Published
- 2023
- Full Text
- View/download PDF
21. MALAT1 expression is associated with aggressive behavior in indolent B-cell neoplasms.
- Author
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Fernández-Garnacho EM, Nadeu F, Martín S, Mozas P, Rivero A, Delgado J, Giné E, López-Guillermo A, Duran-Ferrer M, Salaverria I, López C, Beà S, Demajo S, Jares P, Puente XS, Martín-Subero JI, Campo E, and Hernández L
- Subjects
- Humans, Genes, Neoplasm, Prognosis, Tumor Microenvironment genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Lymphoma, Follicular genetics, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism
- Abstract
MALAT1 long non-coding RNA has oncogenic roles but has been poorly studied in indolent B-cell neoplasms. Here, MALAT1 expression was analyzed using RNA-seq, microarrays or qRT-PCR in primary samples from clinico-biological subtypes of chronic lymphocytic leukemia (CLL, n = 266), paired Richter transformation (RT, n = 6) and follicular lymphoma (FL, n = 61). In peripheral blood (PB) CLL samples, high MALAT1 expression was associated with a significantly shorter time to treatment independently from other known prognostic factors. Coding genes expressed in association with MALAT1 in CLL were predominantly related to oncogenic pathways stimulated in the lymph node (LN) microenvironment. In RT paired samples, MALAT1 levels were lower, concordant with their acquired increased independency of external signals. Moreover, MALAT1 levels in paired PB/LN CLLs were similar, suggesting that the prognostic value of MALAT1 expression in PB is mirroring expression differences already present in LN. Similarly, high MALAT1 expression in FL predicted for a shorter progression-free survival, in association with expression pathways promoting FL pathogenesis. In summary, MALAT1 expression is related to pathophysiology and more aggressive clinical behavior of indolent B-cell neoplasms. Particularly in CLL, its levels could be a surrogate marker of the microenvironment stimulation and may contribute to refine the clinical management of these patients., (© 2023. Springer Nature Limited.)
- Published
- 2023
- Full Text
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22. Molecular map of chronic lymphocytic leukemia and its impact on outcome.
- Author
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Knisbacher BA, Lin Z, Hahn CK, Nadeu F, Duran-Ferrer M, Stevenson KE, Tausch E, Delgado J, Barbera-Mourelle A, Taylor-Weiner A, Bousquets-Muñoz P, Diaz-Navarro A, Dunford A, Anand S, Kretzmer H, Gutierrez-Abril J, López-Tamargo S, Fernandes SM, Sun C, Sivina M, Rassenti LZ, Schneider C, Li S, Parida L, Meissner A, Aguet F, Burger JA, Wiestner A, Kipps TJ, Brown JR, Hallek M, Stewart C, Neuberg DS, Martín-Subero JI, Puente XS, Stilgenbauer S, Wu CJ, Campo E, and Getz G
- Subjects
- Humans, Immunoglobulin Variable Region genetics, Mutation, Prognosis, Genomics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2022
- Full Text
- View/download PDF
23. Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features.
- Author
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Robbe P, Ridout KE, Vavoulis DV, Dréau H, Kinnersley B, Denny N, Chubb D, Appleby N, Cutts A, Cornish AJ, Lopez-Pascua L, Clifford R, Burns A, Stamatopoulos B, Cabes M, Alsolami R, Antoniou P, Oates M, Cavalieri D, Gibson J, Prabhu AV, Schwessinger R, Jennings D, James T, Maheswari U, Duran-Ferrer M, Carninci P, Knight SJL, Månsson R, Hughes J, Davies J, Ross M, Bentley D, Strefford JC, Devereux S, Pettitt AR, Hillmen P, Caulfield MJ, Houlston RS, Martín-Subero JI, and Schuh A
- Subjects
- Humans, Whole Genome Sequencing, Mutation, Genomics, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
The value of genome-wide over targeted driver analyses for predicting clinical outcomes of cancer patients is debated. Here, we report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom's 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy, refining conventional outcome prediction. While requiring independent validation, our findings highlight the potential of whole-genome sequencing to inform future risk stratification in chronic lymphocytic leukemia., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
24. Detection of early seeding of Richter transformation in chronic lymphocytic leukemia.
- Author
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Nadeu F, Royo R, Massoni-Badosa R, Playa-Albinyana H, Garcia-Torre B, Duran-Ferrer M, Dawson KJ, Kulis M, Diaz-Navarro A, Villamor N, Melero JL, Chapaprieta V, Dueso-Barroso A, Delgado J, Moia R, Ruiz-Gil S, Marchese D, Giró A, Verdaguer-Dot N, Romo M, Clot G, Rozman M, Frigola G, Rivas-Delgado A, Baumann T, Alcoceba M, González M, Climent F, Abrisqueta P, Castellví J, Bosch F, Aymerich M, Enjuanes A, Ruiz-Gaspà S, López-Guillermo A, Jares P, Beà S, Capella-Gutierrez S, Gelpí JL, López-Bigas N, Torrents D, Campbell PJ, Gut I, Rossi D, Gaidano G, Puente XS, Garcia-Roves PM, Colomer D, Heyn H, Maura F, Martín-Subero JI, and Campo E
- Subjects
- Cell Transformation, Neoplastic genetics, Disease Progression, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)
high -B cell receptor (BCR)low -signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT., (© 2022. The Author(s).)- Published
- 2022
- Full Text
- View/download PDF
25. IGLV3-21R110 identifies an aggressive biological subtype of chronic lymphocytic leukemia with intermediate epigenetics.
- Author
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Nadeu F, Royo R, Clot G, Duran-Ferrer M, Navarro A, Martín S, Lu J, Zenz T, Baumann T, Jares P, Puente XS, Martín-Subero JI, Delgado J, and Campo E
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, B-Lymphocytes chemistry, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell classification, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Mutation, Young Adult, DNA Methylation, Genes, Immunoglobulin Light Chain genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Point Mutation
- Abstract
B-cell receptor (BCR) signaling is crucial for chronic lymphocytic leukemia (CLL) biology. IGLV3-21-expressing B cells may acquire a single point mutation (R110) that triggers autonomous BCR signaling, conferring aggressive behavior. Epigenetic studies have defined 3 CLL subtypes based on methylation signatures reminiscent of naïve-like (n-CLL), intermediate (i-CLL), and memory-like (m-CLL) B cells with different biological features. i-CLL carries a borderline IGHV mutational load and significantly higher use of IGHV3-21/IGLV3-21. To determine the clinical and biological features of IGLV3-21R110 CLL and its relationship to these epigenetic subtypes, we characterized the immunoglobulin gene of 584 CLL cases using whole-genome/exome and RNA sequencing. IGLV3-21R110 was detected in 6.5% of cases: 30 (38%) of 79 i-CLLs, 5 (1.7%) of 291 m-CLLs, and 1 (0.5%) of 189 n-CLLs. All stereotype subset 2 cases carried IGLV3-21R110, whereas 62% of IGLV3-21R110 i-CLL cases had nonstereotyped BCR immunoglobulins. IGLV3-21R110 i-CLL had a significantly higher number of SF3B1 and ATM mutations and total number of driver alterations. However, the R110 mutation was the sole alteration in 1 i-CLL and was accompanied only by del(13q) in 3. Although IGHV mutational status varied, IGLV3-21R110 i-CLL transcriptomically resembled n-CLL/unmutated IGHV CLL with a specific signature including WNT5A/B overexpression. In contrast, i-CLL lacking IGLV3-21R110 mirrored m-CLL/mutated IGHV. Patients with IGLV3-21R110 i-CLL had a short time to first treatment and overall survival similar to those of n-CLL/unmutated IGHV patients, whereas patients with non-IGLV3-21R110 i-CLL had a good prognosis similar to that of patients with m-CLL/mutated IGHV. IGLV3-21R110 defines a CLL subgroup with specific biological features and an unfavorable prognosis independent of IGHV mutational status and epigenetic subtype., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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26. Chronic lymphocytic leukemias with trisomy 12 show a distinct DNA methylation profile linked to altered chromatin activation.
- Author
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Tsagiopoulou M, Chapaprieta V, Duran-Ferrer M, Moysiadis T, Psomopoulos F, Kollia P, Papakonstantinou N, Campo E, Stamatopoulos K, and Martin-Subero JI
- Subjects
- Chromatin, Chromosomes, Human, Pair 12 genetics, DNA Methylation, Humans, Trisomy genetics, Chromosome Disorders, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Published
- 2020
- Full Text
- View/download PDF
27. The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome.
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Duran-Ferrer M, Clot G, Nadeu F, Beekman R, Baumann T, Nordlund J, Marincevic-Zuniga Y, Lönnerholm G, Rivas-Delgado A, Martín S, Ordoñez R, Castellano G, Kulis M, Queirós AC, Lee ST, Wiemels J, Royo R, Puiggrós M, Lu J, Giné E, Beà S, Jares P, Agirre X, Prosper F, López-Otín C, Puente XS, Oakes CC, Zenz T, Delgado J, López-Guillermo A, Campo E, and Martín-Subero JI
- Subjects
- DNA Methylation genetics, Epigenesis, Genetic genetics, Gene Expression Regulation, Neoplastic, Humans, Epigenome genetics, Neoplasms
- Abstract
We report a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. Differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive patient-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. Subsequently, we construct a DNA methylation-based mitotic clock called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in the differential diagnosis and prediction of clinical outcome., Competing Interests: COMPETING INTERESTS The authors declare no competing interests.
- Published
- 2020
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28. Genomic and epigenomic insights into the origin, pathogenesis, and clinical behavior of mantle cell lymphoma subtypes.
- Author
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Nadeu F, Martin-Garcia D, Clot G, Díaz-Navarro A, Duran-Ferrer M, Navarro A, Vilarrasa-Blasi R, Kulis M, Royo R, Gutiérrez-Abril J, Valdés-Mas R, López C, Chapaprieta V, Puiggros M, Castellano G, Costa D, Aymerich M, Jares P, Espinet B, Muntañola A, Ribera-Cortada I, Siebert R, Colomer D, Torrents D, Gine E, López-Guillermo A, Küppers R, Martin-Subero JI, Puente XS, Beà S, and Campo E
- Subjects
- Adult, Aged, Aged, 80 and over, Cell Proliferation, Cyclin D1 genetics, DNA Methylation, Female, Gene Expression Regulation, Neoplastic, Genomics, Humans, Immunoglobulins genetics, Lymphoma, Mantle-Cell pathology, Male, Middle Aged, Epigenesis, Genetic, Gene Rearrangement, Lymphoma, Mantle-Cell genetics, Mutation
- Abstract
Mantle cell lymphoma (MCL) is a mature B-cell neoplasm initially driven by CCND1 rearrangement with 2 molecular subtypes, conventional MCL (cMCL) and leukemic non-nodal MCL (nnMCL), that differ in their clinicobiological behavior. To identify the genetic and epigenetic alterations determining this diversity, we used whole-genome (n = 61) and exome (n = 21) sequencing (74% cMCL, 26% nnMCL) combined with transcriptome and DNA methylation profiles in the context of 5 MCL reference epigenomes. We identified that open and active chromatin at the major translocation cluster locus might facilitate the t(11;14)(q13;32), which modifies the 3-dimensional structure of the involved regions. This translocation is mainly acquired in precursor B cells mediated by recombination-activating genes in both MCL subtypes, whereas in 8% of cases the translocation occurs in mature B cells mediated by activation-induced cytidine deaminase. We identified novel recurrent MCL drivers, including CDKN1B, SAMHD1, BCOR, SYNE1, HNRNPH1, SMARCB1, and DAZAP1. Complex structural alterations emerge as a relevant early oncogenic mechanism in MCL, targeting key driver genes. Breakage-fusion-bridge cycles and translocations activated oncogenes (BMI1, MIR17HG, TERT, MYC, and MYCN), generating gene amplifications and remodeling regulatory regions. cMCL carried significant higher numbers of structural variants, copy number alterations, and driver changes than nnMCL, with exclusive alterations of ATM in cMCL, whereas TP53 and TERT alterations were slightly enriched in nnMCL. Several drivers had prognostic impact, but only TP53 and MYC aberrations added value independently of genomic complexity. An increasing genomic complexity, together with the presence of breakage-fusion-bridge cycles and high DNA methylation changes related to the proliferative cell history, defines patients with different clinical evolution., (© 2020 by The American Society of Hematology.)
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- 2020
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29. Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma.
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Ordoñez R, Kulis M, Russiñol N, Chapaprieta V, Carrasco-Leon A, García-Torre B, Charalampopoulou S, Clot G, Beekman R, Meydan C, Duran-Ferrer M, Verdaguer-Dot N, Vilarrasa-Blasi R, Soler-Vila P, Garate L, Miranda E, San José-Enériz E, Rodriguez-Madoz JR, Ezponda T, Martínez-Turrilas R, Vilas-Zornoza A, Lara-Astiaso D, Dupéré-Richer D, Martens JHA, El-Omri H, Taha RY, Calasanz MJ, Paiva B, San Miguel J, Flicek P, Gut I, Melnick A, Mitsiades CS, Licht JD, Campo E, Stunnenberg HG, Agirre X, Prosper F, and Martin-Subero JI
- Subjects
- Cell Line, DNA-Binding Proteins metabolism, Epigenesis, Genetic, Humans, NF-kappa B metabolism, Osteogenesis genetics, Receptors, Notch metabolism, Signal Transduction, TOR Serine-Threonine Kinases metabolism, Thioredoxins metabolism, Transcription Factors metabolism, Tumor Suppressor Protein p53 metabolism, Up-Regulation, Chromatin metabolism, Gene Expression Regulation, Neoplastic, Multiple Myeloma genetics, Plasma Cells metabolism
- Abstract
Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin ( TXN ), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype., (© 2020 Ordoñez et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2020
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30. DNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy.
- Author
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Tsagiopoulou M, Papakonstantinou N, Moysiadis T, Mansouri L, Ljungström V, Duran-Ferrer M, Malousi A, Queirós AC, Plevova K, Bhoi S, Kollia P, Oscier D, Anagnostopoulos A, Trentin L, Ritgen M, Pospisilova S, Stavroyianni N, Ghia P, Martin-Subero JI, Pott C, Rosenquist R, and Stamatopoulos K
- Subjects
- Adult, Aged, Cyclophosphamide pharmacology, Disease Progression, Epigenesis, Genetic drug effects, Female, Gene Regulatory Networks drug effects, Humans, Immunotherapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Longitudinal Studies, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Rituximab pharmacology, Treatment Outcome, Vidarabine pharmacology, Vidarabine therapeutic use, Cyclophosphamide therapeutic use, DNA Methylation drug effects, High-Throughput Nucleotide Sequencing methods, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Rituximab therapeutic use, Vidarabine analogs & derivatives
- Abstract
Background: In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen., Results: The extent of identified changes in CLL cells versus memory B cells from healthy donors was termed "epigenetic burden" (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed "relapse changes" (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology., Conclusions: Overall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features.
- Published
- 2019
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31. Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia.
- Author
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Papakonstantinou N, Ntoufa S, Tsagiopoulou M, Moysiadis T, Bhoi S, Malousi A, Psomopoulos F, Mansouri L, Laidou S, Papazoglou D, Gounari M, Pasentsis K, Plevova K, Kuci-Emruli V, Duran-Ferrer M, Davis Z, Ek S, Rossi D, Gaidano G, Ritgen M, Oscier D, Stavroyianni N, Pospisilova S, Davi F, Ghia P, Hadzidimitriou A, Belessi C, Martin-Subero JI, Pott C, Rosenquist R, and Stamatopoulos K
- Subjects
- Apoptosis genetics, Epigenomics methods, Female, Gene Expression Profiling methods, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Primary Cell Culture, Promoter Regions, Genetic genetics, RNA, Small Interfering metabolism, Sequence Analysis, RNA, Transcription Factors metabolism, Tumor Cells, Cultured, Tumor Suppressor Proteins metabolism, Up-Regulation, DNA Methylation genetics, Gene Expression Regulation, Neoplastic, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Receptors, Antigen, B-Cell metabolism, Transcription Factors genetics, Tumor Suppressor Proteins genetics
- Abstract
Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U-CLL). Subset #6 (IGHV1-69/IGKV3-20) is less aggressive compared to subset #8 (IGHV4-39/IGKV1(D)-39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U-CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional nonsubset U-CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro-survival effect was also supported by siRNA-mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness., (© 2018 UICC.)
- Published
- 2019
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32. The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia.
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Beekman R, Chapaprieta V, Russiñol N, Vilarrasa-Blasi R, Verdaguer-Dot N, Martens JHA, Duran-Ferrer M, Kulis M, Serra F, Javierre BM, Wingett SW, Clot G, Queirós AC, Castellano G, Blanc J, Gut M, Merkel A, Heath S, Vlasova A, Ullrich S, Palumbo E, Enjuanes A, Martín-García D, Beà S, Pinyol M, Aymerich M, Royo R, Puiggros M, Torrents D, Datta A, Lowy E, Kostadima M, Roller M, Clarke L, Flicek P, Agirre X, Prosper F, Baumann T, Delgado J, López-Guillermo A, Fraser P, Yaspo ML, Guigó R, Siebert R, Martí-Renom MA, Puente XS, López-Otín C, Gut I, Stunnenberg HG, Campo E, and Martin-Subero JI
- Subjects
- B-Lymphocytes metabolism, Base Sequence, Cohort Studies, Humans, Chromatin metabolism, Epigenomics, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.
- Published
- 2018
- Full Text
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33. In silico deconvolution and purification of cancer epigenomes.
- Author
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Duran-Ferrer M, Beekman R, and Martín-Subero JI
- Abstract
Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.
- Published
- 2017
- Full Text
- View/download PDF
34. Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage.
- Author
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Queirós AC, Beekman R, Vilarrasa-Blasi R, Duran-Ferrer M, Clot G, Merkel A, Raineri E, Russiñol N, Castellano G, Beà S, Navarro A, Kulis M, Verdaguer-Dot N, Jares P, Enjuanes A, Calasanz MJ, Bergmann A, Vater I, Salaverría I, van de Werken HJG, Wilson WH, Datta A, Flicek P, Royo R, Martens J, Giné E, Lopez-Guillermo A, Stunnenberg HG, Klapper W, Pott C, Heath S, Gut IG, Siebert R, Campo E, and Martín-Subero JI
- Subjects
- B-Lymphocytes metabolism, Cell Line, Tumor, Cell Lineage, Computer Simulation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Humans, SOXC Transcription Factors genetics, DNA Methylation, Enhancer Elements, Genetic, Epigenomics methods, High-Throughput Nucleotide Sequencing methods, Lymphoma, Mantle-Cell genetics
- Abstract
We analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal-center-inexperienced and germinal-center-experienced B cells, and we found that DNA methylation profiles during lymphomagenesis are largely influenced by the methylation dynamics in normal B cells. An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11. Finally, we observed that the magnitude of DNA methylation changes per case is highly variable and serves as an independent prognostic factor for MCL outcome., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
35. Whole-genome fingerprint of the DNA methylome during human B cell differentiation.
- Author
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Kulis M, Merkel A, Heath S, Queirós AC, Schuyler RP, Castellano G, Beekman R, Raineri E, Esteve A, Clot G, Verdaguer-Dot N, Duran-Ferrer M, Russiñol N, Vilarrasa-Blasi R, Ecker S, Pancaldi V, Rico D, Agueda L, Blanc J, Richardson D, Clarke L, Datta A, Pascual M, Agirre X, Prosper F, Alignani D, Paiva B, Caron G, Fest T, Muench MO, Fomin ME, Lee ST, Wiemels JL, Valencia A, Gut M, Flicek P, Stunnenberg HG, Siebert R, Küppers R, Gut IG, Campo E, and Martín-Subero JI
- Subjects
- Base Sequence, Cell Differentiation, Cells, Cultured, CpG Islands, Gene Expression Regulation, Leukemic, Genome, Human, Humans, Leukemia, B-Cell genetics, Sequence Analysis, DNA, B-Lymphocytes physiology, DNA Methylation, Epigenesis, Genetic immunology
- Abstract
We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.
- Published
- 2015
- Full Text
- View/download PDF
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