DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control

Kretzmer, Helene; Bernhart, Stephan H.; Wang, Wei; Haake, Andrea; Weniger, Marc A.; Bergmann, Anke; Betts, Matthew J.; Pau, Enrique Carrillo de Santa; Doose, Gero; Gutwein, Jana; Richter, Julia; Hovestadt, Volker; Huang, Bingding; Rico, Daniel; Jühling, Frank; Kolarova, Julia; Lu, Qianhao; Otto, Christian; Wagener, Rabea; Arnolds, Judith; Burkhardt, Birgit; Claviez, Alexander; Drexler, Hans; Eberth, Sonja; Eils, Roland; Flicek, Paul; Haas, Siegfried; Hummel, Michael; Karsch, Dennis; Kerstens, Hinrik H.D.; Klapper, Wolfram; Kreuz, Markus; Lawerenz, Chris; Lenze, Dido; Loeffler, Markus; López, Cristina; MacLeod, Roderick A.F.; Martens, Joost H.A.; Kulis, Marta; Martín‐Subero, José I.; Möller, Peter; Nagel, Inga; Picelli, Simone; Vater, Inga; Rohde, Marius; Rosenstiel, Philip; Rosołowski, Maciej; Russell, Robert B.; Schilhabel, Markus B.; Schlesner, Matthias; Stadler, Peter F.; Szczepanowski, Monika; Trümper, Lorenz; Stunnenberg, Hendrik G.; Küppers, Ralf; Ammerpohl, Ole; Lichter, Peter; Siebert, Reiner; Hoffmann, Steve; Radlwimmer, Bernhard

doi:10.1038/ng.3413

Cited by 122 publications

(128 citation statements)

References 54 publications

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…Remarkably, all of these samples belonged to the ABC-DLBCL subtype and carried a copy number gain of 18q detected by both fluorescent in situ hybridization with a BCL2-specific probe and somatic copy number variant mapping. 26,27 A critical role for BCL2, particularly in activated B cells, is further corroborated by published transcriptome analyses. Specifically, BCL2 mRNA was not expressed in GCB cells but was massively induced during activation of peripheral blood B cells.…”

Section: Resultsmentioning

confidence: 49%

B-cell–specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice

Knittel

Liedgens

Korovkina

et al. 2016

Blood

Self Cite

View full text Add to dashboard Cite

Key Points• B-cell-specific expression of Myd88 p.L252P leads to the development of DLBCL in mice.• The Myd88 p.L252P mutation cooperates with BCL2 amplifications in ABC-DLBCL lymphomagenesis in vivo.The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-kB activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-kB pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2. Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88 p.L252P (the orthologous position of the human MYD88 p.L265P mutation) from the endogenous locus.These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2. Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently cooccurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL. (Blood. 2016;127(22):2732-2741

show abstract

Section: Resultsmentioning

confidence: 49%

B-cell–specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice

Knittel

Liedgens

Korovkina

et al. 2016

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…These newly defined tumor-specific (ts) DMRs were consistent between different patients and accurately distinguished normal from tumor tissue. The tsDMRs transcend the considerable global differences in DNA methylation between each cell type, since, unlike CAFs, cancer cells undergo extensive hypomethylation (Hansen et al 2011;Berman et al 2012;Kretzmer et al 2015). Notably, the tsDMRs are strongly overrepresented in developmental gene families and genes involved in endocrine hormone secretion, such as TBX3 (Holterhus et al 2007;Beukers et al 2015), suggesting that they are associated with functional roles in cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Enduring epigenetic landmarks define the cancer microenvironment

et al. 2018

View full text Add to dashboard Cite

The growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment. To date, molecular profiling has largely been restricted to the epithelial component of tumors; therefore, features underpinning the persistent protumorigenic phenotype of the tumor microenvironment are unknown. Using whole-genome bisulfite sequencing, we show for the first time that cancer-associated fibroblasts (CAFs) from localized prostate cancer display remarkably distinct and enduring genome-wide changes in DNA methylation, significantly at enhancers and promoters, compared to nonmalignant prostate fibroblasts (NPFs). Differentially methylated regions associated with changes in gene expression have cancer-related functions and accurately distinguish CAFs from NPFs. Remarkably, a subset of changes is shared with prostate cancer epithelial cells, revealing the new concept of tumor-specific epigenome modifications in the tumor and its microenvironment. The distinct methylome of CAFs provides a novel epigenetic hallmark of the cancer microenvironment and promises new biomarkers to improve interpretation of diagnostic samples.

show abstract

“…Differences in DNA methylation levels have also been connected to many different diseases like diabetes (Nilsson et al 2014) or Alzheimer's disease (De Jager et al 2014). Furthermore, differential DNA methylation plays a role in many cancers, such as medulloblastoma (Hovestadt et al 2014) and B-cell lymphoma (Kretzmer et al 2015), and connects risk factors like age (Teschendorff et al 2010) and smoking (Teschendorff et al 2015) with cancer.…”

mentioning

confidence: 99%

metilene: fast and sensitive calling of differentially methylated regions from bisulfite sequencing data

et al. 2015

Self Cite

View full text Add to dashboard Cite

The detection of differentially methylated regions (DMRs) is a necessary prerequisite for characterizing different epigenetic states. We present a novel program, metilene, to identify DMRs within whole-genome and targeted data with unrivaled specificity and sensitivity. A binary segmentation algorithm combined with a two-dimensional statistical test allows the detection of DMRs in large methylation experiments with multiple groups of samples in minutes rather than days using off-the-shelf hardware. metilene outperforms other state-of-the-art tools for low coverage data and can estimate missing data. Hence, metilene is a versatile tool to study the effect of epigenetic modifications in differentiation/development, tumorigenesis, and systems biology on a global, genome-wide level. Whether in the framework of international consortia with dozens of samples per group, or even without biological replicates, it produces highly significant and reliable results.

show abstract

DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control

Cited by 122 publications

References 54 publications

B-cell–specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice

B-cell–specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice

Enduring epigenetic landmarks define the cancer microenvironment

metilene: fast and sensitive calling of differentially methylated regions from bisulfite sequencing data

Contact Info

Product

Resources

About