The t(2;3)(q21;q27) translocation in non-Hodgkin's lymphoma displays BCL6 mutations in the 5′ regulatory region and chromosomal breakpoints distant from the gene

Chen, Weiyi; Butler, Margaret H.; Rao, Pulivarthi H.; Chaganti, Seeta R.; Louie, Diane C.; Dalla‐Favera, Riccardo; Chaganti, R. S. K.

doi:10.1038/sj.onc.1202098

Cited by 23 publications

(20 citation statements)

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“…We found that the nucleotide sequences of the ES and IS regions in the BCL6 gene (Bernardin et al, 1997) are highly conserved between humans and mice (100% homology in ES and 65.9% in IS). In addition, the deletions within the BCL6 gene in the ®ve cases of lymphomas previously reported were also found to occur in the ®rst exon-intron boundary region spanning ES and IS (Bernardin et al, 1997;Chen et al, 1998;Nakamura et al, 1996;1999). These observations strongly suggest that the ES and IS regions have important roles in the transcriptional regulation of the BCL6 gene, and their alteration may be a crucial event in lymphomagenesis.…”

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confidence: 56%

Identification of negative regulatory regions within the first exon and intron of the BCL6 gene

et al. 2000

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Chromosomal translocations involving BCL6 gene are frequent in human B-cell lymphomas. Chromosomal breaks preferentially occur within a 3-kb region containing the ®rst exon and intron. Recent reports have revealed that internal deletions or point mutations also are common in this region, suggesting that structural alteration of this region may be a crucial event in the development of lymphomas. In this study, we identi®ed two regions in the BCL6 gene that negatively regulate BCL6 expression. One region, ES, is located within the ®rst exon between nucleotides +472 and +543, and a second region, IS, is located between +783 and +918 of the ®rst intron. A consensus nucleotide sequence for the binding of the BCL6 protein itself was found within the ES region. An electrophoretic mobility shift assay and a co-transfection experiment using a BCL6 expression vector showed that transcription of the BCL6 gene was negatively regulated by the BCL6 gene product. The IS region which is included in the regions commonly deleted in B-cell lymphomas had a silencer activity. Structural alterations of these two regions may play roles in the deregulated expression of the BCL6 gene in B-cell lymphomas. Oncogene (2000) 19, 4941 ± 4945.Keywords: BCL6; B-cell lymphoma; silencer element A chromosomal translocation involving 3q27 is one of the most common cytogenetic abnormalities in human B-cell lymphomas. The BCL6 gene, encoding a zinc®nger transcriptional repressor, has been isolated from the breakpoint at 3q27 (Baron et al., 1993;Kerckaert et al., 1993;Miki et al., 1994;Ye et al., 1993). The translocation preferentially occurs within a 3-kb region spanning the ®rst exon-intron boundary. The promoter region and ®rst non-coding exon are replaced by other genes including the immunoglobulin (Ig) genes, and the resulting deregulated expression of BCL6 may contribute to lymphomagenesis.Recent studies have found that some lymphomas carry internal deletions (Bernardin et al., 1997;Nakamura et al., 1996;1999), and more frequently, point mutations Gaidano et al., 1997;Liang et al., 1998;Migliazza et al., 1995) within the BCL6 gene. Interestingly, the deletions and mutations preferentially occur within the ®rst exonintron boundary region, the same region in which the breakpoints for chromosomal translocation cluster. These observations suggest that the structural alteration of this region, which may contain regulatory sequences, is a crucial event in the development of Bcell lymphomas.To investigate the functional signi®cance of the ®rst exon-intron boundary region on the transcriptional regulation of the BCL6 gene, luciferase reporter constructs carrying various genomic fragments of this region were transfected transiently into Raji cells, expressing endogenous BCL6 ( Figure 1A). pBCL7657/471Luc, containing the region from 7657 to +471, showed signi®cant luciferase activity in Raji cells, as previously reported (Ohashi et al., 1995). We arbitrarily de®ned the luciferase activity of pBCL7657/471Luc as 100% and used this as a reference to normali...

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confidence: 56%

Identification of negative regulatory regions within the first exon and intron of the BCL6 gene

et al. 2000

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“…13,43,44 This study aimed at defining the incidence of BCL6 gene alterations in the different subgroups of DLBCL as defined by GEP. In addition, we have (10) 4 (40%) 6 (60%) UNCL (27) 10 (37%) 17 (63%) Total (138) 78 (56%) 60 (44%)…”

Section: Discussionmentioning

confidence: 99%

“…8 Briefly, a BCL6 break-apart probe (BAP; Abbott-Vysis, Downers Grove, IL, USA) was used to detect BCL6 translocations at major breakpoint region (MBR) and a BCL6 home-brew BAP (Clone RP11-1144D2 and RP11-67E18) at the alternative breakpoint region (ABR) (78/133 cases). 27,28 Nuclei were counterstained with 4,6-diamidino-2-phenylindole (DAPI) in Antifade solution and the slides were visualized using an Olympus BX51 fluorescence microscope. Images were captured and archived using Cyto Vision software (Applied Imaging, Santa Clara, CA, USA).…”

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confidence: 99%

Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma

et al. 2007

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Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed biologically and prognostically distinct subgroups: germinal center B-cell-like (GCB), activated B-celllike (ABC) and primary mediastinal (PM) DLBCL. The BCL6 gene is often translocated and/or mutated in DLBCL. Therefore, we examined the BCL6 molecular alterations in these DLBCL subgroups, and their impact on BCL6 expression and BCL6 target gene repression. BCL6 translocations at the major breakpoint region (MBR) were detected in 25 (18.8%) of 133 DLBCL cases, with a higher frequency in the PM (33%) and ABC (24%) subgroups than in the GCB (10%) subgroup. Translocations at the alternative breakpoint region (ABR) were detected in five (6.4%) of 78 DLBCL cases, with three cases in ABC and one case each in the GCB and the unclassifiable subgroups. The translocated cases involved IgH and non-IgH partners in about equal frequency and were not associated with different levels of BCL6 mRNA and protein expression. BCL6 mutations were detected in 61% of DLBCL cases, with a significantly higher frequency in the GCB and PM subgroups (470%) than in the ABC subgroup (44%). Exon-1 mutations were mostly observed in the GCB subgroup. The repression of known BCL6 target genes correlated with the level of BCL6 mRNA and protein expression in GCB and ABC subgroups but not with BCL6 translocation and intronic mutations. No clear inverse correlation between BCL6 expression and p53 expression was observed. Patients with higher BCL6 mRNA or protein expression had a significantly better overall survival. The biological role of BCL6 in translocated cases where repression of known target genes is not demonstrated is intriguing and warrants further investigation.

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“…Chromosomal translocations involving the 3q27 region have been already recognized as B-NHL-related abnormalities occurring in approximately 40% of DLBCL and in 5% to 10% of follicular lymphomas. 61,62 The t(3q27) results in a deregulation of the BCL6 proto-oncogene, encoding a zinc finger transcription repressor either by the Ig gene clusters at 2p12, 14q32, and 22q11, or by a variety of other genomic loci. [63][64][65] It has been shown that the BCL6 protein is expressed predominantly in normal GC B cells and related lymphomas, and is required for GC formation and function.…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte predominance Hodgkin disease is characterized by recurrent genomic imbalances

Franke

Włodarska

Maes

et al. 2001

Blood

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IntroductionHodgkin disease (HD), one of the most common malignant lymphomas in the western world, was first described by Thomas Hodgkin in 1832. The characteristic morphologic feature of HD is the cellular composition of the tumor tissue containing a small number (approximately 0.1% to 1%) of neoplastic ReedSternberg (RS) cells and a major population of nonneoplastic lymphocytes, histiocytes, neutrophils, fibroblasts, eosinophils, and plasma cells. On the basis of tumor cell morphology, immunophenotype, and the composition of the cellular background, 2 separate biologic entities, namely, lymphocyte predominance Hodgkin disease (LPHD) (or nodular paragranuloma) and classical HD have been recognized in the Revised European-American Lymphoma (REAL) classification. 1 LPHD accounts for 5% of all HD cases. Typically, patients are 25-to 45-year-old men and usually present at an early clinical stage. More than 90% of patients with LPHD have a complete response to therapy, although recurrences frequently occur. In LPHD, a particular variant of RS cells, the "popcorn" or lymphocytic and histiocytic (L&H) cells, is found. In contrast to RS cells of classical HD, "popcorn" cells lack the expression of CD30 and CD15 but express CD45 and CD20. The expression of these markers and presence of nodular structures closely resembling lymphoid B follicles have suggested that "popcorn" cells represent neoplastic germinal center B cells. [2][3][4] Because of the very low frequency of RS and "popcorn" cells in the tumor tissue and the lack of suitable methods for their purification and analysis, clonality and lineage derivation of neoplastic cells in HD have remained uncertain until recently. As soon as single-cell polymerase chain reaction (PCR)-based methods had been developed, clonal Ig rearrangement and consistent occurrence of somatic mutations within the variableregions of Ig genes amplified from isolated RS and "popcorn" cells have been demonstrated in the majority of analyzed cases. These findings indicated a clonal germinal-center (GC) or post-GC B-cell origin of LPHD as well as of classical HD. [5][6][7][8][9][10][11] On the other hand, polyclonal Ig rearrangements found in some HD cases 12-14 led to the hypothesis of a sequential poly-/oligo-/monoclonal origin of HD, a matter that is still under discussion. [15][16] Despite recent progress in HD research, genetic and molecular data are only scarcely available. There are intrinsic technical problems in obtaining metaphase chromosomes in HD (low number of RS cells, low proliferation index, infiltration of reactive cells), and therefore no more than 200 HD cases with [19][20][21] and by comparative genomic hybridization (CGH), 22,23 so far no specific cytogenetic marker(s) could be identified. Single RScell PCR analysis of CMYC, BCL2, and BCL1 suggested that these non-Hodgkin lymphoma (NHL)-specific genes are not involved in the pathogenesis of HD. 24,25 Even less is known about genetic and molecular aberrations in the LP subtype of HD. To the best of our knowledge, only 9 LP...

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The t(2;3)(q21;q27) translocation in non-Hodgkin's lymphoma displays BCL6 mutations in the 5′ regulatory region and chromosomal breakpoints distant from the gene

Cited by 23 publications

References 21 publications

Identification of negative regulatory regions within the first exon and intron of the BCL6 gene

Identification of negative regulatory regions within the first exon and intron of the BCL6 gene

Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma

Lymphocyte predominance Hodgkin disease is characterized by recurrent genomic imbalances

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