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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromosomal translocation affecting the 3q27 band, where the BCL6 gene is localized, is one of the most common genetic abnormalities in non-Hodgkin's lymphoma of B-cell type (B-NHL). The translocation occurs within the major translocation cluster (MTC) of BCL6, and as the result of translocation either one of the three immunoglobulin (Ig) genes or a heterogeneous non-Ig gene is juxtaposed to the coding regions of BCL6. On the other hand, somatic hypermutation involves the BCL6 gene of not only B-NHL but also B-cells from normal individuals. The mutations are clustered within a region of the MTC, suggesting that a common molecular mechanism is operating for the two genetic lesions of BCL6. The Bcl-6 protein is a transcriptional repressor that is an important regulator of lymphoid development and function. The protein is preferentially expressed in germinal center (GC) B-cells of normal lymphoid tissues as well as in a variety of B-NHL subtypes derived from GC B-cells irrespective of whether the BCL6 is rearranged. Although there is no consensus on the effect of BCL6 translocation on the clinical outcome of B-NHL, many studies coincide in showing that a high-level of BCL6 expression at either or both the mRNA and protein levels is a favorable prognostic marker of diffuse large B-cell lymphoma. In vitro evidence suggests that non-Ig/BCL6 translocation transiently enhances the level of Bcl-6 expression, which may perturb a molecular network that controls the differentiation of GC B-cells to Ig-secreting plasma cells, thereby predisposing the B-cells to neoplastic transformation.
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PMID:Pathogenetic role of BCL6 translocation in B-cell non-Hodgkin's lymphoma. 1502 21

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed prognostically important subgroups: germinal center B-cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal large B-cell lymphoma. The t(14;18)(q32;q21) has been reported previously to define a unique subset within the GCB-DLBCL. We evaluated for the translocation in 141 cases of DLBCL that were successfully gene expression profiled. Using a dual-probe fluorescence in situ hybridization assay, we detected the t(14;18) in 17% of DLBCLs and in 34% of the GCB subgroup which contained the vast majority of positive cases. In addition, 12 t(14;18)-positive cases detected by polymerase chain reaction assays on additional samples were added to the fluorescence in situ hybridization-positive cases for subsequent analysis. Immunohistochemical data indicated that BCL2, BCL6, and CD10 protein were preferentially expressed in the t(14;18)-positive cases as compared to t(14;18)-negative cases. Within the GCB subgroup, the expression of BCL2 and CD10, but not BCL6, differed significantly between cases with or without the t(14;18): 88% versus 24% for BCL2 and 72% versus 32% for CD10, respectively. In the GCB-DLBCL subgroup, a heterogeneous group of genes is overexpressed in the t(14;18)-positive subset, among which BCL2 is a significant discriminator. Interestingly, the t(14;18)-negative subset is dominated by overexpression of cell cycle-associated genes, indicating that these tumors are significantly more proliferative, suggesting distinctive pathogenetic mechanisms. However, despite this higher proliferative activity, there was no significant difference in overall or failure-free survival between the t(14;18)-positive and -negative subsets within the GCB subgroup.
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PMID:BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma. 1521 71

Mantle cell lymphoma is routinely considered as a Bcl6-negative B-cell lymphoma carrying the translocation t(11;14). Here we describe a series of five Bcl6-positive mantle cell lymphoma cases, including three classic and two blastoid variants. The proliferative index of these cases, measured with the Ki-67 antibody, was slightly higher than in Bcl6-negative mantle cell lymphoma cases (32.2 vs. 23.7%) Bcl6 expression was associated with translocations involving 3q27 in four of the five cases and an extra copy of the BCL6 gene in the fifth. A mutational study of the major mutational cluster in the BCL6 gene revealed no increased mutation rate, except in one case. One of the three cases displayed a high mutational index in the IgVH gene, suggesting exposure to a germinal center microenvironment. Chromosomal alterations involving 3q27 seem to be responsible for this increased Bcl6 expression, which needs to be considered when Bcl6 is used in lymphoma diagnosis.
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PMID:Aberrant Bcl6 protein expression in mantle cell lymphoma. 1525 12

The present study aimed to characterize the clinical and molecular-cytogenetic features of non-Hodgkin's lymphoma (NHL) with double translocation of the immunoglobulin heavy chain (IGH) gene. G-banding analysis, fluorescence in situ hybridization (FISH) with the IGH (Cgamma and VH) and oncogene (c-MYC, BCL1, BCL2, and BCL6) probes, and long-distance polymerase chain reaction (LD-PCR) were performed on 6 patients with B-cell lymphoma, one with angioimmunoblastic T-cell lymphoma, and one with acute lymphoblastic leukemia (ALL) with B-cell phenotype. G-banding analysis detected two different 14q32 translocations, t(14,18) and add (14)(q32) in a patient with ALL. Two distinct partners of double IGH translocation identified by FISH were as follows: c-MYC + BCL2 in 3 patients, c-MYC + BCL1 in 2, c-MYC + BCL6 in one, BCL2 + 9q22 in one, and 1q21 + 6q27 in one. Colocalization of BCL1 and c-MYC probes was demonstrated in a patient with mantle cell lymphoma. LD-PCR detected c-MYC/Cmu, c-MYC/Calpha and BCL6/Cmu, and c-MYC/Calpha fusion in each one patient. Seven of 8 patients showed high serum LDH. Central nervous system and leukemic involvement was observed in 5 and 6 patients, respectively. Median survival time of patients with c-MYC/IGH translocation was 9 months. The results defined a clinical subset of B-cell lymphoma/leukemia showing extremely poor prognosis. C-MYC/IGH translocation is possibly an evolutionary alteration following the primary IGH translocation with BCL1, BCL2, or BCL6. Furthermore, FISH identified one novel (9q22) and one cryptic chromosomal breakpoints (6q27) involved in IGH translocation.
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PMID:Molecular-cytogenetic characterization of non-Hodgkin's lymphoma with double and cryptic translocations of the immunoglobulin heavy chain gene. 1537 Feb 7

The human proto-oncogene BCL6 encodes a BTB/POZ-zinc-finger transcriptional repressor that is necessary for germinal-centre formation and is implicated in the pathogenesis of B-cell lymphoma. The precise function of BCL6 in germinal-centre development and lymphomagenesis is unclear because very few direct BCL6 target genes have been identified. Here we report that BCL6 suppresses the expression of the p53 (also known as tp53) tumour suppressor gene and modulates DNA damage-induced apoptotic responses in germinal-centre B cells. BCL6 represses p53 transcription by binding two specific DNA sites within the p53 promoter region and, accordingly, p53 expression is absent in germinal-centre B cells where BCL6 is highly expressed. Suppression of BCL6 expression via specific short interfering RNA leads to increased levels of p53 messenger RNA and protein both under basal conditions and in response to DNA damage. Most notably, constitutive expression of BCL6 protects B cell lines from apoptosis induced by DNA damage. These results suggest that an important function of BCL6 is to allow germinal-centre B cells to tolerate the physiological DNA breaks required for immunoglobulin class switch recombination and somatic hypermutation without inducing a p53-dependent apoptotic response. These findings also imply that deregulated BCL6 expression contributes to lymphomagenesis in part by functional inactivation of p53.
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PMID:The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. 1557 13

The BCL6 transcriptional repressor is normally expressed during the germinal center phase of B-cell differentiation. Germinal center B-cells typically undergo rapid proliferation in spite of accumulating DNA damage caused by class switch recombination and somatic hypermutation. BCL6 is required to license B-cells for the germinal center reaction and its down regulation appears to be important for cells to exit this stage and undergo further differentiation. BCL6 appears to mediate these biological effects by recruiting corepressor complexes to silence critical cell cycle checkpoint and differentiation related genes. Based on our data and recent publications, we propose that these gene pathways are regulated through distinct transcriptional mechanisms, which can be specifically targeted to reprogram B-cells preferentially for either growth suppression and apoptosis, or differentiation. As BCL6 plays a central role in the pathogenesis of diffuse large B-cell lymphoma, we predict that targeting BCL6 transcriptional repression complexes in malignant B-cells may constitute a novel form of transcription therapy for lymphomas and possibly other tumors.
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PMID:Reprogramming specific gene expression pathways in B-cell lymphomas. 1565 67

We identified the human germinal center-associated lymphoma (HGAL) in gene-expression profiling studies of diffuse large B-cell lymphoma (DLBCL). The expression of HGAL correlated with survival in patients with DLBCL. The HGAL gene is the human homolog of M17, a mouse gene expressed specifically in normal germinal center (GC) B cells. We generated a monoclonal antibody against the HGAL protein and show that HGAL is expressed in the cytoplasm of GC lymphocytes and in lymphomas of GC derivation. Among 727 lymphomas tested by immunohistochemistry on tissue microarrays, HGAL staining was found in follicular lymphomas (103 of 107), Burkitt lymphomas (40 of 40), mediastinal large B lymphomas (7 of 8), and in DLBCLs (103 of 151). Most marginal zone lymphomas lacked HGAL staining. Lymphocyte-predominant Hodgkin lymphomas (12 of 17) and, surprisingly, classical Hodgkin lymphomas (78 of 107) were found to be positive. Hierarchical clustering of comparative immunohistologic results in DLBCLs demonstrates that the expression of HGAL is similar to 2 other GC-associated proteins, BCL6 and CD10, but different from 2 markers associated with a non-GC phenotype, MUM1/IRF4 and BCL2. The restricted expression and GC specificity of HGAL protein suggest that it may have an important role in the diagnosis of specific lymphomas, and, potentially in the identification of subtypes associated with different prognoses.
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PMID:Expression of the human germinal center-associated lymphoma (HGAL) protein, a new marker of germinal center B-cell derivation. 1567 69

In contrast to nodal large B-cell lymphomas, recurrent chromosomal aberrations have been studied only in a small number of cases of primary cutaneous diffuse large B-cell lymphoma (PCDLBCL). We investigated 25 PCDLBCLs (classified according to the WHO-EORTC classification into PCDLBCL, leg-type, 8; and PCDLBCL, other, 17), using an interphase fluorescence in situ hybridization technique. All cases were analyzed for chromosomal aberrations commonly observed in nodal large B-cell lymphomas, including structural aberrations of the genes BCL2, BCL6, and c-MYC, and numerical aberrations of the chromosomes/genes 3, 7, 8, 11, 12, 13, 17, 18q, RB1, and p53. We observed genetic aberrations in 19 (76%) of 25 patients. The most frequent numerical aberrations were gains of chromosome 12 (7 of 25, 28%), 7 (5 of 25, 20%), 3 (5 of 25, 20%), 18q (3 of 25, 12%), 11 (3 of 25, 12%), X (3 of 25, 12%), and losses of chromosome/gene 17/p53 (3 of 25, 12%). BCL2, c-MYC, and BCL6 were rearranged with the IGH gene in 4 (16%), 1 (4%), and none (0%) of 25 cases, respectively. Most aberrations were homogeneously distributed among cases of PCDLBCL, leg-type and of PCDLBCL, other, cases located on the leg or at other body sites, cases with round and cleaved cell morphology, and Bcl-2+ and Bcl-2- cases. These results suggest that PCDLBCLs show similar chromosomal aberrations irrespective of classification, anatomic site, cell morphology, and Bcl-2 expression, and that many similarities between primary cutaneous and nodal diffuse large B-cell lymphomas can be observed.
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PMID:Genetic aberrations in primary cutaneous large B-cell lymphoma: a fluorescence in situ hybridization study of 25 cases. 1583 92

The transcription factor PU.1 has been shown to be crucial for the early stages of B cell development but its function at later stages of B cell development is less well known. We observed previously that PU.1 is expressed uniformly throughout the mature pre-plasma cell B cell population, the only exception being a subpopulation of germinal centre (GC) cells which showed exceptionally high expression of PU.1. This suggested that PU.1 may also have a role in GC B cell biology. To test this hypothesis and to screen for possible genes regulated by PU.1, we first evaluated semi-quantitatively the possible co-expression of PU.1 with proteins known to be upregulated or downregulated during GC B cell development. Normal lymphoid tissues and 255 B cell non-Hodgkin lymphomas of putative GC B cell origin were evaluated. PU.1 expression was positively associated with CD10 (p < 0.0001), CD20 (p = 0.043), CD22 (p = 0.005), CD79a (p = 0.024) and Bcl-6 (p < 0.0001) and negatively associated with cytoplasmic immunoglobulin light-chain expression (p = 0.036) in diffuse large B cell lymphoma. Identical or nearly identical associations were found in follicular lymphoma. Since CD20 is known to be partly regulated by PU.1 and putative PU.1-binding sites have been described in the regulatory regions of the CD22, CD79a and CD10 genes, we looked for putative PU.1 binding sites in the BCL6 promotor. Four such putative PU.1 binding sites were identified. Further analysis by gel-shift electromobility essay showed that PU.1 protein binds to three of the four putative binding sites in the BCL6 promotor. PU.1 and Bcl-6 were also found to be upregulated in centroblasts in the normal GC, but jointly downregulated in a subpopulation of centrocytes. Our findings support the contention that PU.1 may also have an important role in GC B cell development.
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PMID:PU.1 protein expression has a positive linear association with protein expression of germinal centre B cell genes including BCL-6, CD10, CD20 and CD22: identification of PU.1 putative binding sites in the BCL-6 promotor. 1684 70

Cytogenetic and fluorescence in situ hybridization (FISH) analysis of an aggressive undifferentiated soft tissue sarcoma diagnosed as primitive neuroectodermal tumor (PNET) revealed an insertion ins(4;X)(q31-32;p11p22) as the sole aberration. To identify the molecular genetic consequences, contigs of bacterial artificial chromosomes (BACs) covering Xp11-p22 and 4q31-32 were constructed. The breakpoint in Xp22 was considered unlikely to be of pathogenetic significance, as it was very close to the Xp telomere, a region devoid of known or predicted genes. The breakpoint in Xp11 was mapped within a BAC clone containing BCOR, encoding a BCL6 (B-cell lymphoma 6)-interacting protein that may influence apoptosis, as the only known gene. FISH analysis with three overlapping clones on normal chromosomes 4 disclosed that the insertion of Xp11 material in der(4) was accompanied by a deletion of chromosome 4 material. Only a predicted gene (XM_094074) was shown to be partially included in the deletion. This gene displays a high similarity with the gene encoding the embryonic blastocoelar extracellular matrix (ECM) protein in sea urchin, which is involved in the migration of the primary mesenchyme cells during embryogenesis. Our results suggest that BCOR and/or an ECM-like protein could be involved in the pathogenesis of a subgroup of PNET or PNET-like sarcomas.
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PMID:Molecular cytogenetic characterization of an ins(4;X) occurring as the sole abnormality in an aggressive, poorly differentiated soft tissue sarcoma. 1613 67


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