Base-pair resolution DNA methylome of the EBV-positive Endemic Burkitt lymphoma cell line DAUDI determined by SOLiD bisulfite-sequencing

Kreck, Benjamin; Richter, Julia; Ammerpohl, Ole; Barann, Matthias; Esser, Daniela; Petersen, Britt‐Sabina; Vater, Inga; Penas, Eva Maria Murga; Chung, Christina A. Bormann; Seisenberger, Stefanie; Boyd, Victoria L.; Smallwood, Sébastien A.; Drexler, Hans G.; MacLeod, Roderick A.F.; Hummel, Michael; Krueger, Felix; Häsler, Robert; Schreiber, Stefan; Rosenstiel, Philip; Franke, André; Siebert, Reiner

doi:10.1038/leu.2013.4

Cited by 28 publications

(13 citation statements)

References 21 publications

(25 reference statements)

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“…In the case of FL, MCL, Burkitt lymphoma, and CLL/SLL, genome-wide comparison of the methylome of lymphoma cells with that of putative normal counterparts revealed some differences of DNA methylation in terms of the genome-wide distribution and/or individual genes. [8][9][10][11][12][13] However, a distinct global status of 5 hmC in relation to 5 mC in FL, MCL, Burkitt lymphoma, and CLL/SLL has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Distinct Global DNA Methylation Status in B-Cell Lymphomas : Immunohistochemical Study of 5-Methylcytosine and 5-Hydroxymethylcytosine

Matsuda

Imai

Hirota

2014

J Clin Exp Hematopathol

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Lymphomas are malignant neoplasms composed of lymphoid cells at various developmental stages and lineages. Recent advances in comprehensive genomic analyses in acute myeloid leukemia have revealed prevalent mutations in regulators of epigenetic phenomena including global DNA methylation status. The examples include mutations in isocitrate dehydrogenase 1 (IDH1), IDH2, and ten-eleven translocation 2. These mutations are proposed to inhibit conversion of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC), leading to global accumulation of 5 mC. These changes in global DNA methylation status can be visualized immunohistochemically using specific antibodies against 5 mC and 5 hmC. We examined the global DNA methylation status of B-cell lymphomas and that of their normal counterparts by immunohistochemistry for 5 mC and 5 hmC. Non-tumor lymphoid cells inside germinal centers (GC) in reactive lymphoid hyperplasia (RLH) were stained positive for 5 mC, but they were negative for 5 hmC. Similarly, follicular lymphomas, whose postulated normal counterparts are centrocytes in GCs, were 5 mC-positive but 5 hmC-negative by immunohistochemistry. This immunostaining pattern was also observed in Burkitt lymphoma. In contrast, non-tumor lymphoid cells in mantle zones were stained positive for 5 mC as well as for 5 hmC. Likewise, most mantle cell lymphomas, whose postulated normal counterparts are mantle zone B cells in RLH, were stained positive for 5 mC as well as for 5 hmC. This immunostaining pattern was also observed in chronic lymphocytic leukemia/small lymphocytic lymphoma. These results suggest that, in terms of 5 mC/5 hmC immunohistochemistry, B-cell lymphomas with different histological subtypes are associated with distinct global DNA methylation statuses that resemble those of their postulated normal counterparts.

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Section: Discussionmentioning

confidence: 99%

Distinct Global DNA Methylation Status in B-Cell Lymphomas : Immunohistochemical Study of 5-Methylcytosine and 5-Hydroxymethylcytosine

Matsuda

Imai

Hirota

2014

J Clin Exp Hematopathol

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“…To investigate whether the BL-genotype with the corresponding mutations in the BL-specific (onco)genes still affects BCR signaling, we characterized BCR signaling in the BL cell line Daudi. Daudi cells genetically differ from DG75 cells because they harbor an inactivating ID3 mutation (4,15), but have in common with DG75 cells that they (i) depend on BCR signaling ( Fig. 2A) and (ii) express similar amounts of BCR on their surface (Fig.…”

Section: Resultsmentioning

confidence: 99%

Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

Corso

Pan

Walter

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified ∼16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeletonrelated processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments.lymphoma | B-cell receptor | phosphoproteome | cancer biology

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“…Two other less frequently used fragile zones, the 105-bp BCL2-icr and 561-bp BCL2-mcr (the two starburst symbols at the right), account for 13% and 5% of BCL2 translocation breakpoints, respectively. A detailed view of the breakpoint distribution within the BCL2-MBR is presented with a triangle at each of the patient breakpoint sites from der (14) of the t(14;18) plotted above the sequence, and those identified from der (18) are plotted below the sequence. The breakpoints within the fragile zone are clustered around the CG DNA sequence motif (highlighted by red).…”

Section: Methodsmentioning

confidence: 99%

Human Lymphoid Translocation Fragile Zones Are Hypomethylated and Have Accessible Chromatin

Lieber

Tsai

et al. 2015

Molecular and Cellular Biology

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Chromosomal translocations are a hallmark of hematopoietic malignancies. CG motifs within translocation fragile zones (typically 20 to 600 bp in size) are prone to chromosomal translocation in lymphomas. Here we demonstrate that the CG motifs in human translocation fragile zones are hypomethylated relative to the adjacent DNA. Using a methyltransferase footprinting assay on isolated nuclei (in vitro), we find that the chromatin at these fragile zones is accessible. We also examined in vivo accessibility using cellular expression of a prokaryotic methylase. Based on this assay, which measures accessibility over a much longer time interval than is possible with in vitro methods, these fragile zones were found to be more accessible than the adjacent DNA. Because DNA within the fragile zones can be methylated by both cellular and exogenous methyltransferases, the fragile zones are predominantly in a duplex DNA conformation. These observations permit more-refined models for why these zones are 100-to 1,000-fold more prone to undergo chromosomal translocation than the adjacent regions.C hromosomal translocations are seminal events in the development of many hematologic malignancies (1). Many hematopoietic malignancies are associated with recurrent reciprocal translocations and their resulting gene fusions or amplifications, which guide diagnosis, assessment of prognosis, and treatment. One example is the BCL2-IGH translocation, t(14;18)(q32;q21), observed in 85% of follicular lymphomas (FL) and 30% of diffuse large B cell lymphomas (DLBCL). A second example is the CCND1-IGH translocation, t(11;14)(q13;q32), observed in almost all mantle cell lymphomas (MCL). Oncogenes near sites of recurrent translocation often confer a selective growth advantage (2). For unknown reasons, human chromosomal translocation breakpoints near these oncogenes frequently cluster within tight DNA zones (often only 20 to 600 bp in length) known as fragile zones (see the green starbursts in the upper portion of Fig. 1A and 2A). These zones are 100-to 1,000-fold more sensitive to breakage than the adjacent DNA regions located, for example, only 20 bp to either side of the fragile zone (2-7). Hence, the DNA sequences surrounding each oncogene are not equally sensitive to breakage. The molecular basis for such an extreme breakage propensity within such a short zone of DNA is unknown, despite our progress on elucidation of other aspects of the mechanism described below (8).We have previously reported that breakpoints of human lymphoid translocation fragile zones are not randomly distributed (Fig. 1A and 2A). Pro-B/pre-B cell-stage translocations show a breakage propensity for the CG (commonly called CpG but designated CG in this paper) DNA sequence motif within the 20 to 600-bp fragile zones (3). We have proposed a model in which activation-induced deaminase (AID) initiates double-strand breaks (DSBs) by acting at the methylated form of these CG sites in single-stranded DNA (ssDNA) to deaminate the 5-methylcytosine to yield a T-G mismatch (3). The r...

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Base-pair resolution DNA methylome of the EBV-positive Endemic Burkitt lymphoma cell line DAUDI determined by SOLiD bisulfite-sequencing

Cited by 28 publications

References 21 publications

Distinct Global DNA Methylation Status in B-Cell Lymphomas : Immunohistochemical Study of 5-Methylcytosine and 5-Hydroxymethylcytosine

Distinct Global DNA Methylation Status in B-Cell Lymphomas : Immunohistochemical Study of 5-Methylcytosine and 5-Hydroxymethylcytosine

Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

Human Lymphoid Translocation Fragile Zones Are Hypomethylated and Have Accessible Chromatin

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