Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

• Published in: Cancer cell 2016-11, Vol.30 (5), p.806-821
• Main Authors: Queirós, Ana C., Beekman, Renée, Vilarrasa-Blasi, Roser, Duran-Ferrer, Martí, Clot, Guillem, Merkel, Angelika, Raineri, Emanuele, Russiñol, Nuria, Castellano, Giancarlo, Beà, Sílvia, Navarro, Alba, Kulis, Marta, Verdaguer-Dot, Núria, Jares, Pedro, Enjuanes, Anna, Calasanz, María José, Bergmann, Anke, Vater, Inga, Salaverría, Itziar, van de Werken, Harmen J.G., Wilson, Wyndham H., Datta, Avik, Flicek, Paul, Royo, Romina, Martens, Joost, Giné, Eva, Lopez-Guillermo, Armando, Stunnenberg, Hendrik G., Klapper, Wolfram, Pott, Christiane, Heath, Simon, Gut, Ivo G., Siebert, Reiner, Campo, Elías, Martín-Subero, José I.
• Format: Article
• Language: English
• Subjects: B-Lymphocytes - metabolism; Cell Line, Tumor; Cell Lineage; ChIP-seq; chromatin; Computer Simulation; DNA looping; DNA Methylation; enhancer; Enhancer Elements, Genetic; Epigenesis, Genetic; epigenomics; Epigenomics - methods; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing - methods; Humans; lymphoma; Lymphoma, Mantle-Cell - genetics; mantle cell lymphoma; SOX11; SOXC Transcription Factors - genetics; whole-genome bisulfite sequencing
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2016.09.014

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. [Display omitted] •Epigenetic imprints of normal B cell subpopulations identify two subtypes of MCL•Dynamically methylated regions in normal B cells acquire additional changes in MCL•Identification of distant enhancers of oncogenes as potential epigenetic drivers•Epigenetic heterogeneity in MCL is linked to genetic changes and clinical behavior As part of the IHEC consortium, Queirós et al. perform an epigenomic analysis of mantle cell lymphoma, which reveals two major subtypes with distinct clinicobiological features and identifies distant enhancers as potential epigenetic drivers. Explore the Cell Press IHEC web portal www.cell.com/consortium/IHEC.