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B H Ye

Publications and source records attributed to B H Ye.

At least 19 recordsLinked to original sources
PubMed1998

Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor.

The bcl-6 proto-oncogene encodes a POZ/zinc finger transcriptional repressor expressed in germinal center (GC) B and T cells and required for GC formation and antibody affinity maturation. Deregulation of bcl-6 expression by chromosomal rearrangements and point mutations of the bcl-6 promoter region are implicated in the pathogenesis of B-cell lymphoma. The signals regulating bcl-6 expression are not known. Here we show that antigen receptor activation leads to BCL-6 phosphorylation by mitogen-activated protein kinase (MAPK). Phosphorylation, in turn, targets BCL-6 for rapid degradation by the ubiquitin/proteasome pathway. These findings indicate that BCL-6 expression is directly controlled by the antigen receptor via MAPK activation. This signaling pathway may be crucial for the control of B-cell differentiation and antibody response and has implications for the regulation of other POZ/zinc finger transcription factors in other tissues.

B-Lymphocytes↗
PubMed1997

The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation.

Structural alterations of the promoter region of the BCL-6 proto-oncogene represent the most frequent genetic alteration associated with non-Hodgkin lymphoma, a malignancy often deriving from germinal-centre B cells. The BCL-6 gene encodes a zinc-finger transcriptional repressor normally expressed in both B cells and CD4+ T cells within germinal centres, but its precise function is unknown. We show that mice deficient in BCL-6 displayed normal B-cell, T-cell and lymphoid-organ development but have a selective defect in T-cell-dependent antibody responses. This defect included a complete lack of affinity maturation and was due to the inability of follicular B cells to proliferate and form germinal centres. In addition, BCL-6-deficient mice developed an inflammatory response in multiple organs characterized by infiltrations of eosinophils and IgE-bearing B lymphocytes typical of a Th2-mediated hyperimmune response. Thus, BCL-6 functions as a transcriptional switch that controls germinal centre formation and may also modulate specific T-cell-mediated responses. Altered expression of BCL-6 in lymphoma represents a deregulation of the pathway normally leading to B cell proliferation and germinal centre formation.

Animals↗
PubMed1996

BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor.

Approximately 40% of diffuse large cell lymphoma are associated with chromosomal translocations that deregulate the expression of the BCL6 gene by juxtaposing heterologous promoters to the BCL-6 coding domain. The BCL6 gene encodes a 95-kDa protein containing six C-terminal zinc-finger motifs and an N-terminal POZ domain, suggesting that it may function as a transcription factor. By using a DNA sequence selected for its ability to bind recombinant BCL-6 in vitro, we show here that BCL-6 is present in DNA-binding complexes in nuclear extracts from various B-cell lines. In transient transfectin experiments, BCL6 can repress transcription from promoters linked to its DNA target sequence and this activity is dependent upon specific DNA-binding and the presence of an intact N-terminal half of the protein. We demonstrate that this part of the BCL6 molecule contains an autonomous transrepressor domain and that two noncontiguous regions, including the POZ motif, mediate maximum transrepressive activity. These results indicate that the BCL-6 protein can function as a sequence-specific transcriptional repressor and have implications for the role of BCL6 in normal lymphoid development and lymphomagenesis.

3T3 Cells↗
PubMed1996

Monoclonal antibodies PG-B6a and PG-B6p recognize, respectively, a highly conserved and a formol-resistant epitope on the human BCL-6 protein amino-terminal region.

The human BCL-6 gene, which is rearranged in approximately 30% of diffuse large B cell lymphomas, encodes a 706-amino-acid nuclear protein of the Kruppel-type zinc finger transcription factors mainly expressed in normal germinal center B cells and related lymphomas. Four monoclonal antibodies (PG-B6, PG-B6a, PG-B6p, and PG-B6m), specifically directed against the human BCL-6 protein, were generated by immunizing BALB/c mice with a recombinant protein corresponding to the BCL-6 amino-terminal region (amino acids 3 to 484). The PG-B6 monoclonal antibody reacted with a BCL-6 epitope sensitive to fixatives and preserved in all mammalian species. PG-B6a (a is for avian) recognized the most evolutionarily conserved BCL-6 epitope (expressed in all animal species including avian). PG-B6p (p is for paraffin) recognized a fixative-resistant epitope of BCL-6 that was detectable on paraffin sections after microwave heating in 1 mmol/L EDTA buffer. PG-B6m (m is for mantle) was the least specific monoclonal antibody as, in addition to BCL-6, it reacted with a yet undefined antigen selectively located in the cytoplasm of mantle and marginal zone B cells. All monoclonal antibodies detected strong nuclear expression of BCL-6 in follicular lymphomas, diffuse large B cell lymphomas, Burkitt's lymphomas, and nodular, lymphocyte-predominance Hodgkin's disease. In diffuse large B cell lymphomas, BCL-6 expression was independent of BCL-6 gene rearrangements and did not correlate with expression of other markers or the proliferation index. BCL-6 was not expressed in B-CLL, hairy cell leukemia, mantle-cell- and marginal-zone-derived lymphomas. Labeling of paraffin sections with PG-B6p proved useful for differentiating proliferation centers in B-CLL (BCl-2+/BCL-6-) from trapped germinal centers in mantle cell lymphomas (BCL-2-/BCL-6+) and for identifying neoplastic cells in cases of nodular, lymphocyte-predominance Hodgkin's disease. Because of their high specificity, wide reactivity in humans and animal species including avians (PG-B6a), and suitability for labeling routine paraffin sections (PG-B6p), the reagents described in this paper should prove valuable in both research and diagnostics.

Amino Acid Sequence↗
PubMed1995

Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma.

The BCL6 gene encodes a zinc-finger transcription factor and is altered by chromosomal arrangements in its 5' noncoding region in approximately 30% of diffuse large-cell lymphoma (DLCL). We report here that, in 22/30 (73%) DLCL and 7/15 (47%) follicular lymphoma (FL), but not in other tumor types, the BCL6 gene is also altered by multiple (1.4 x 10(-3) -1.6 x 10(-2) per bp), often biallelic, mutations clustering in its 5' noncoding region. These mutations are of somatic origin and are found in cases displaying either normal or rearranged BLC6 alleles indicating their independence from chromosomal rearrangements and linkage to immunoglobulin genes. These alterations identify a mechanism of genetic instability in malignant B cells and may have been selected during lymphomagenesis for their role in altering BCL6 expression.

Alleles↗
PubMed1995

Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma.

The BCL6 gene codes for a zinc-finger transcription factor and is involved in chromosomal rearrangements in 30-40% of diffuse large-cell lymphoma (DLCL). These rearrangements cluster within the 5' regulatory region of BCL6 spanning its first non-coding exon. To determine the functional consequences of these alterations, we have analyzed the structure of the rearranged BCL6 alleles and their corresponding RNA and protein species in two DLCL biopsies and one tumor cell line which carried the t(3;14)(q27;q32) translocation involving the BCL6 and immunoglobulin heavy-chain (IgH) loci. In all three cases, the breakpoints were mapped within the IgH switch region and the BCL6 first intron, leading to the juxtaposition of part of the IgH locus upstream and in the same transcriptional orientation to the BCL6 coding exons. An analysis of cDNA clones showed that these recombinations generate chimeric IgH-BCL6 transcripts which initiated from IgH germline transcript promoters (I mu or I gamma 3), but retain a normal BCL6 coding domain. In the tumor cell line, the chimeric I gamma 3-BCL6 allele, but not the germline BCL6 gene, was transcriptionally active and produced a normal BCL6 protein. These findings indicate that t(3;14) translocations alter BCL6 expression by promoter substitution and imply that the consequence of these alterations is the deregulated expression of a normal BCL6 protein.

Alleles↗
PubMed1995

BCL-6 protein is expressed in germinal-center B cells.

Structural alterations of the 5' noncoding region of the BCL-6 gene have been found in 40% of diffuse large cell lymphoma (DLCL) and 5% to 10% of follicular lymphomas (FL), suggesting that deregulated BCL-6 expression may play a role in lymphomagenesis. Nucleotide sequencing of BCL-6 cDNA predicted a protein containing six zinc-finger domains, suggesting that it may function as a transcription factor. Using antisera raised against N- and C-terminal BCL-6 synthetic oligopeptides in immunoprecipitation, immunoblot, and immunocytochemical assays, this study identifies the BCL-6 gene product as a 95-kD nuclear protein. Western blot analysis of human tumor cell lines representative of various hematopoietic lineages/stages of differentiation showed that the BCL-6 protein is predominantly expressed in the B-cell lineage where it was found in mature B cells. Immunohistochemical analysis of normal human lymphoid tissues indicated that BCL-6 expression is topographically restricted to germinal centers including all centroblasts and centrocytes. The BCL-6 protein was also detectable in inter- and intra-follicular CD4+ T cells, but not in other follicular components including mantle-zone B cells, plasma cells, dendritic cells, and macrophages. Immunohistochemical analysis of DLCL and FL biopsy samples showed that the BCL-6 protein is detectable in these tumors independent of the presence of BCL-6 gene rearrangements. These results indicate that the expression of the BCL-6 gene is specifically regulated during B-cell differentiation and suggest a role for BCL-6 in germinal center development or function. Because DLCL derive from germinal-center B cells, deregulated BCL-6 expression may contribute to lymphomagenesis by preventing postgerminal center differentiation.

Amino Acid Sequence↗
PubMed1995

A specific monoclonal antibody (PG-B6) detects expression of the BCL-6 protein in germinal center B cells.

The BCL-6 gene is frequently involved in translocations occurring at the 3q27 locus and is rearranged in approximately 30% of diffuse large cell lymphomas and in a small fraction of follicular lymphomas. The BCL-6 gene encodes for a Kruppel-type zinc-finger protein, the cell/tissue expression and function of which is unknown. In this study, we describe a new monoclonal antibody (PG-B6) that is specifically directed against a fixative-sensitive epitope on the amino-terminal region of the BCL-6 protein. By immunocytochemical analysis, BCL-6 localizes in the nucleus where PG-B6 staining gives a microgranular/diffuse pattern with exclusion of the nucleoli. The main reactivity of PG-B6 in tonsil and spleen is with the nuclei of germinal center B cells, whereas B cells within the mantle and marginal zones do not express BCL-6. No other lymphoid cells in the tonsil express BCL-6 except for a subset of CD3+/CD4+ intrafollicular and interfollicular T cells. A few lymphoid cells of unknown phenotype express BCL-6 in the thymus. Extra-lymphoid BCL-6 expression includes a weak nuclear positivity of epithelia. In non-Hodgkin's lymphomas, BCL-6 expression parallels that observed in normal lymphoid compartments, eg, expression in germinal center-derived tumors (follicular and diffuse large cell lymphomas), but not in mantle cell and marginal zone lymphomas. In most diffuse large cell lymphomas, the BCL-6 protein is expressed at high levels in cases with or without BCL-6 gene rearrangements. These findings indicate that BCL-6 expression is specifically regulated during B lymphocyte development and suggest that BCL-6 may play a role during B cell differentiation in the germinal center.

Animals↗
PubMed1994

Rearrangements of the BCL-6 gene in acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma: association with diffuse large-cell subtype.

Acquired immunodeficiency syndrome (AIDS)-associated non-Hodgkin's lymphomas (AIDS-NHL), a major source of morbidity and mortality among AIDS patients, are derived from B cells and can be classified into two main histologic categories, small noncleaved cell lymphoma (SNCCL) and diffuse large-cell lymphoma (DLCL). DLCL includes two histologic subsets, ie, large noncleaved cell lymphoma (LNCCL) and large cell-immunoblastic plasmacytoid lymphoma (LC-IBPL). Several studies have shown that AIDS-SNCCL is associated with the clonal accumulation of multiple genetic lesions, including Epstein-Barr virus (EBV) infection, activation of the c-MYC and RAS oncogenes, as well as inactivation of the p53 tumor suppressor gene at variable frequencies. On the contrary, the molecular pathogenesis of AIDS-DLCL is largely obscure, because no genetic lesion other than EBV infection has been specifically identified in this group. In this study, we have tested a panel of 40 AIDS-NHL for structural alterations of BCL-6, a putative proto-oncogene that is frequently altered in DLCL in the immunocompetent host. Our results show that rearrangements of BCL-6 are present in 20% of AIDS-DLCL (5 of 24), including 2 of 8 LNCCL and 3 of 16 LC-IBPL, but in no case of AIDS-SNCCL. BCL-6 rearrangements were detected both in the presence and in the absence of EBV infection of the tumor clone, but in no case were associated with activation of c-MYC or mutations of p53. These data identify a novel genetic lesion in AIDS-DLCL and corroborate the notion that lymphomagenesis in AIDS follows two distinct molecular pathways that are associated with the development of histologically distinct types of AIDS-NHL.

DNA-Binding Proteins↗
PubMed1994

Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma.

BACKGROUND: About 40 percent of non-Hodgkin's lymphomas are diffuse lymphomas with a large-cell component (DLLC). Current therapy can induce a long-term remission in half the patients with DLLC, but more intensive treatment has the potential to improve outcome, particularly in patients at high risk for treatment failure. Clinical and cytogenetic markers can identify subgroups at high or low risk. Rearrangement of a novel candidate proto-oncogene, bcl-6, is a possible prognostic indicator in DLLC. METHODS: We performed Southern blot hybridization to detect bcl-6 and bcl-2 gene rearrangement in samples of lymphoma from 102 patients with B-cell DLLC. The results were correlated with the patients' histologic features, age, disease stage, tumor sites and bulk of disease, serum lactate dehydrogenase level, and treatment outcome. RESULTS: Rearranged bcl-6 was found in 23 cases, and rearranged bcl-2 in 21 cases. Nineteen of the patients with rearranged bcl-6 had extranodal DLLC, two had primary splenic lymphomas, and only one had bone marrow involvement. Thirty-six months after diagnosis, the proportion with freedom from progression of disease was projected to be 82 percent (95 percent confidence interval, 66 to 98 percent) among the patients with rearranged bcl-6, as compared with 56 percent (95 percent confidence interval, 43 to 70 percent) for the patients with germ-line bcl-6 and bcl-2 and 31 percent (95 percent confidence interval, 8 to 53 percent) for the patients with rearranged bcl-2. The status of the bcl-6 gene was an independent prognostic marker of survival and freedom from disease progression in a multivariate model and added predictive value to established prognostic signs. CONCLUSIONS: Rearrangement of the bcl-6 gene correlated with a favorable clinical outcome in DLLC and may thus serve as a prognostic marker in patients with this form of malignant lymphoma.

Aged↗
PubMed1994

Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma.

The pathogenesis of non-Hodgkin's lymphoma (NHL) with a large cell component (DLLC, including diffuse large cell, DLCL; diffuse mixed cell, MX-D; and immunoblastic, IMB) is unknown. A novel candidate proto-oncogene, BCL6, that is involved in chromosome band 3q27 aberrations in NHL has been recently identified. We have investigated the incidence and disease-specificity of BCL6 rearrangements in a large panel of lymphoid tumors, including acute and chronic lymphoid leukemias (96 cases), various NHL types (125 cases), and multiple myelomas (23 cases). BCL6 rearrangements were found in 16/45 (35.5%) DLLC, more frequently in DLCL (15/33, 45%) than in MX-D (1/10, 10%), in 2/31 (6.4%) follicular NHL, and in no other tumor types. BCL6 rearrangements represent the first genetic lesion specifically and recurrently associated with DLLC and should prove useful for understanding the pathogenesis as well as for the clinical monitoring of these tumors.

DNA-Binding Proteins↗
PubMed1994

Identification of genetic lesions associated with diffuse large-cell lymphoma.

BACKGROUND: The pathogenesis of several subtypes of non-Hodgkin's lymphoma (NHL) is associated with specific genetic lesions involving oncogenes and tumor-suppressor genes. These lesions include c-myc translocation and p53 inactivation in small noncleaved-cell lymphoma, and bcl-2 and bcl-1 translocation in follicular (FL) and mantle-zone lymphoma, respectively. Relatively little is known, however, about the pathogenesis of diffuse lymphoma with a large-cell component (DLLC; including large-, mixed-cell, and immunoblastic), the most relevant NHL type in terms of morbidity and mortality. Since DLLC can occur 'de novo' or via histologic transformation of follicular lymphoma, it is critical to identify lesions associated with both pathogenetic pathways. DESIGN: The present work is aimed at (i) identifying the role of cytogenetic and molecular lesions involving oncogenes or tumor-suppressor genes in the transformation of FL into DLLC in a series of 5 patients for whom sequential biopsies were available pre- and post-transformation and (ii) identifying novel proto-oncogenes involved in DLLC pathogenesis by molecular analysis of chromosomal translocations affecting band 3q27, which are common in DLLC. RESULTS: Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL. A novel proto-oncogene, bcl-6, coding for a zinc-finger transcription factor, was cloned from 3q27 breakpoints and shown to be structurally altered in 33% (13/39) of DLLC samples studied, but not in other types of lymphoid malignancies. CONCLUSIONS: These results indicate that inactivation of the p53 tumor-suppressor gene may complement bcl-2 activation and be involved in the transformation of FL into DLLC. Activation of the bcl-6 oncogene may represent one of the steps in the pathogenesis of 'de novo' DLLC. Both lesions should prove useful as diagnostic and prognostic markers in the clinical management of these tumors.

Humans↗
PubMed1994

BCL-6 and the molecular pathogenesis of B-cell lymphoma.

The results presented identify the first genetic lesion associated with DLCL, the most clinically relevant form of NHL. Although no proof yet exists of a role for these lesions in DLCL pathogenesis, the feature of the BCL-6 gene product, its specific pattern of expression in B cells, and the clustering of lesions disrupting its regulatory domain strongly suggest that deregulation of BCL-6 expression may contribute to DLCL development. A more precise definition of the role of BCL-6 in normal and neoplastic B-cell development is the goal of ongoing study of transgenic mice engineered either to express BCL-6 under heterologous promoters or lacking BCL-6 function due to targeted deletions. In addition to contributing to the understanding of DLCL pathogenesis, the identification of BCL-6 lesions may have relevant clinical implications. DLCL represent a heterogeneous group of neoplasms which are treated homogeneously despite the fact that only 50% of patients experience long-term disease-free survival (Schneider et al. 1990). The fact that BCL-6 rearrangements identify biologically and clinically distinct subsets of DLCL suggests that these lesions may be useful as markers in selection of differential therapeutic strategies based on different risk groups. Furthermore, the BCL-6 rearrangements can be used to identify and monitor the malignant clone with sensitive PCR-based techniques. Since clinical remission has been observed in a significant fraction of DLCL cases, these markers may serve as critical tools for sensitive monitoring of minimal residual disease and early diagnosis of relapse (Gribben et al. 1993).

Animals↗
PubMed1994

[The mosquitocidal efficacy of microcapsules of alpha-cypermethrin against Anopheles sinensis].

The efficacy of spraying of alpha-cypermethrin microcapsule for the control of Anopheles sinensis was investigated when alpha-cypermethrin microcapsule was sprayed at 0.5 g/m2, the KT50 was 7.9 min and a 100% of 24 hours' mortality of An. sinensis, the efficacy being similar to that of the emulsion. 180 days after spray, the KT50 was 28.2 min, the 24 hours' mortality was 85.7%, the residual efficacy was 3 times over that of the emulsion. In the mimic field experiment, similar results were obtained. In the field trial, the residual efficacy of the alpha-cypermethrin microcapsule was 5.9 times that of the emulsion. Alpha-cypermethrin microcapsules is recommended as a good formulation of mosquitocide for mosquito control, considering its mosquitocidal efficacy and residual efficacy.

Animals↗
PubMed1993

Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma.

The molecular pathogenesis of diffuse large-cell lymphoma (DLCL), the most frequent and clinically relevant type of lymphoma, is unknown. A gene was cloned from chromosomal translocations affecting band 3q27, which are common in DLCL. This gene, BCL-6, codes for a 79-kilodalton protein that is homologous with zinc finger-transcription factors. In 33 percent (13 of 39) of DLCL samples, but not in other types of lymphoid malignancies, the BCL-6 gene is truncated within its 5' noncoding sequences, suggesting that its expression is deregulated. Thus, BCL-6 may be a proto-oncogene specifically involved in the pathogenesis of DLCL.

Amino Acid Sequence↗
PubMed1993

Cloning of bcl-6, the locus involved in chromosome translocations affecting band 3q27 in B-cell lymphoma.

Chromosomal translocations involving band 3q27 and various chromosomal sites, including the sites of the immunoglobulin (Ig) loci (14q32, 2p12, 22q11), represent recurrent aberrations in non-Hodgkin's lymphoma (NHL). In order to identify the putative protooncogene involved in these translocations, we have cloned the breakpoints from two B-cell NHL cases carrying t(3;14)(q27;q32) translocations by screening genomic DNA libraries constructed from NHL biopsy samples with immunoglobulin probes. Several recombinant phages have been obtained from each case and shown to contain sequences from both 14q32 and 3q27 by fluorescence in situ hybridization mapping on metaphase chromosomes. In both cases, the translocation breakpoints were found within the switch region of the Ig heavy-chain locus on 14q32 and within the same 3-kilobase region on 3q27. When used in Southern blot hybridization, a probe from the 3q27 region detected rearrangements in an additional five NHL cases carrying 3q27 translocations with 14q32 or other genomic sites. The same probe detected a predominant 2.4-kilobase mRNA species in several lymphoid cell lines analyzed by Northern blot hybridization. These data suggest that chromosomal breakpoints in 3q27 cluster in the proximity of a transcribed gene which represents a candidate protooncogene (bcl-6) involved in B-cell NHL pathogenesis.

Chromosomes, Human, Pair 14↗