Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BCL-6 is a novel proto-oncogene that codes for a zinc-finger protein sharing homologies with many transcription factors. It has recently been shown that BCL-6 is involved in chromosome band 3q27 aberrations in non-Hodgkin's lymphomas (NHLs) and BCL-6 rearrangements have been detected in 34-45 per cent of diffuse large cell lymphomas with B immunophenotype. We have studied the BCL-6 gene configuration by Southern blot analysis in 60 cases of B-cell NHL and in 17 cases of Hodgkin's disease (HD). BCL-6 was rearranged in 15/46 (32.6 per cent) diffuse B-large cell lymphomas, mainly with centroblastic morphology, and in 2/11 (18.2 per cent) follicular (centroblastic-centrocytic) lymphomas. Conversely, all cases of HD, including four cases of lymphocyte predominant, nodular type (nodular paragranuloma), had a germline configuration. These findings confirm that BCL-6 is rearranged in a significant percentage of diffuse B-large cell lymphomas, suggesting that this proto-oncogene might have a pathogenetic role in this subset of NHLs, but our preliminary analysis suggests that BCL-6 lesions are not involved in the pathogenesis of HD. However, further investigations using more sensitive techniques are required to confirm these findings.
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PMID:Analysis of the BCL-6 gene configuration in diffuse B-cell non-Hodgkin's lymphomas and Hodgkin's disease. 747 75

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.
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PMID:A specific monoclonal antibody (PG-B6) detects expression of the BCL-6 protein in germinal center B cells. 763 34

The LAZ3 gene encodes a novel zinc-finger protein that shares homology with several Drosophila transcription factors. This gene was identified by its disruption in translocations involving chromosome 3q27 in diffuse large-cell lymphomas. To assess the frequency and role of this gene's involvement in lymphomagenesis and tumor progression, we examined a series of 170 cases of non-Hodgkin's lymphomas of B-cell lineage for LAZ3 gene rearrangement, expression, and mutation. The cases included 35 de novo diffuse aggressive lymphomas (DAL; 19 large-cell, 4 mixed-cell, and 12 large-cell immunoblastic), 52 transformed aggressive lymphomas derived from follicular lymphomas (TFL), 42 indolent follicular lymphomas (FL), 14 mantle cell lymphomas (MCL), and 27 small noncleaved cell lymphomas (SNCL). LAZ3 rearrangements were found in 10 DAL (28.6%), 9 TFL (17.3%), and 6 FL (14.3%), but not in any of the SNCL or MCL. LAZ3 rearrangement was not exclusive of bcl-2 rearrangement. Most rearrangement breakpoints mapped to a 10-kb BamHI-Xba I fragment located 5' to the LAZ3 coding sequence, consistent with previously reported breakpoint locations. Northern analysis of both rearranged and nonrearranged B-cell lymphoma cases showed similar levels of a transcript of approximately 3.8 kb, indicating that LAZ3 is broadly expressed in B-cell tumors and is not confined to rearranged cases. To investigate whether mutation of the LAZ3 gene might contribute to a potential role for this gene in lymphomagenesis, we screened the coding sequences of 13 rearranged cases, 6 nonrearranged cases, and 13 hematopoietic tumor cell lines. Although three probable polymorphisms were identified, mutations were detected in only 2 rearranged cases. Only 1 of these resulted in an amino acid substitution. Two cell lines (SU-DHL4 and Molt-4) also contained mutations; only one resulted in an amino acid substitution. We conclude (1) that LAZ3 rearrangements occur in a significant fraction of de novo DAL as well as in a smaller subset of indolent and transformed follicular lymphomas; (2) that LAZ3 message is expressed in both rearranged and nonrearranged B-cell lymphomas; and (3) that mutation of the LAZ3 gene does not contribute to its putative oncogenic role in most 3q27 translocated B-cell lymphomas.
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PMID:Analysis of LAZ3 (BCL-6) status in B-cell non-Hodgkin's lymphomas: results of rearrangement and gene expression studies and a mutational analysis of coding region sequences. 774 50

We have previously shown that the LAZ3/BCL6 gene encoding a potential transcription factor, is disrupted in B-diffuse large cell non-Hodgkin's lymphomas (NHL) with 3q27 chromosomal abnormalities involving the immunoglobulin (IG) genes. However, LAZ3 rearrangement also occurs in NHL bearing 3q27 translocations without involvement of the IG genes: for example the VAl cell line exhibits t(3;4)(q27;p11). In the present work we have used a RT-PCR method to detect and to sequence the LAZ3 mRNA products from the VAL cell line. We report that the consequence of the t(3;4) is the expression of a chimeric transcript of LAZ3 with a new gene encoding a small G-like protein, termed TTF (Translocation Three Four). Nucleotide sequence analysis of a 1.4 kb cDNA predicts that the TTF gene encodes a protein of 191 amino-acids similar to members of the RAS superfamily including HRAS (27% identical), RAB1A (30% identical) and RHO proteins: the human RAC1, RHOB and CDC42Hs proteins (respectively 43, 44 and 45% identical) and the yeast RHO2 protein (44% identical). Unlike most other small G proteins which are expressed ubiquitously, TTF was transcribed only in hemopoietic cells as a 2.2 kb transcript. TTF may define a new subgroup of RHO-like proteins.
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PMID:TTF, a gene encoding a novel small G protein, fuses to the lymphoma-associated LAZ3 gene by t(3;4) chromosomal translocation. 778 61

The BCL-6 gene is known to be located on chromosome 3q27, at the breakpoint of the 3q27-associated translocations that occur frequently in human non-Hodgkin's lymphomas (NHLs). To identify the BCL-6 protein, two antibodies that recognized distinct domains of this protein were raised in rabbits. Immunoprecipitation and immunoblotting of lysates of BCL-6-expressing cells using both antibodies showed a broad 92- to 98-kD band. Dephosphorylation of BCL-6 protein reduced the size of this band to 87 kD, suggesting that BCL-6 may be expressed in a phosphorylated form. Immunostaining with both antibodies showed that BCL-6 protein was localized in the nuclei of most of the germinal center B cells and a small number of marginal zone B cells. Furthermore, BCL-6 protein was expressed in follicular, Burkitt's, and diffuse large B-cell lymphomas. These results suggest that the BCL-6 protein, expressed in B cells of the germinal centers which are important in the maturation of immune responses, may play some physiological role(s) in the germinal center B cells.
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PMID:BCL-6 gene product, a 92- to 98-kD nuclear phosphoprotein, is highly expressed in germinal center B cells and their neoplastic counterparts. 779 34

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.
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PMID:Rearrangements of the BCL-6 gene in acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma: association with diffuse large-cell subtype. 802 68

Translocation t(3;22)(q27;q11) has recently been recognized as a recurrent abnormality in non-Hodgkin's malignant lymphoma (NHL). A new gene, LAZ3, has been shown to be involved in NHL with 3q27 rearrangement. Two patients with B-cell NHL were studied by chromosome painting and Southern blot analysis. Fluorescence in situ hybridization to metaphase chromosomes was shown to be an easy way to detect the chromosomal abnormality even in metaphase cells with poorly defined chromosomes. The gene LAZ3 was rearranged in one patient in the 'major translocation cluster region'. The comigration of rearranged LAZ3 and of IGL bands suggests that the translocation resulted in the juxtaposition of the two genes. This juxtaposition makes possible a potential deregulation of the LAZ3 gene expression, as previously shown for the MYC and BCL2 genes in Burkitt and follicular lymphoma translocations.
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PMID:Translocation t(3;22)(q27;q11) in non-Hodgkin's malignant lymphoma: chromosome painting and molecular studies. 825 95

Twelve B-cell non-Hodgkin's lymphomas with BCL6/LAZ3 rearrangement selected from a series of 30 lymphomas with cytogenetically detectable 3qter abnormalities were characterized at the histological, clinical, and cytogenetic levels, including fluorescence in situ hybridization (FISH) analysis, which was performed in all cases but one. A classical t(3;14) and t(3;22) were found in three patients (25%). In the remaining cases, eleven different 3q27 abnormalities were demonstrated and characterized with the use of chromosome painting. Seven of twelve "variant" rearrangements identified in our series affecting 1p32, 1p34, 3p14, 6q23, 12p13, 14q11, and 16p13 have not been reported before. Moreover, involvement of both homologs of chromosome 3 in distinct translocations was detected as an unexpected result in two cases and was confirmed via FISH in a third case. The putative bichromosomal rearrangements of the 3q27 region were evidenced by Southern analysis in one of these cases. In another case, FISH with a cosmid spanning the 3q27 breakpoint region demonstrated the involvement of BCL6/LAZ3 only in one of two t(3q27). In our series, which was selected on cytogenetic and molecular criteria, 50% (6 of 12) of cases with BCL6/LAZ3 rearrangement were diagnosed as diffuse, large B-cell lymphomas (DLCL). Another 33% (4 of 12) of cases were diagnosed as follicular center lymphomas (FL), with t(14;18)/BCL2 rearrangement in all but one case. Furthermore, in three follicular lymphoma cases in which multiple samples were analyzed, the disease showed no evidence of histological progression during a follow-up period of 3-14 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fluorescence in situ hybridization identifies new chromosomal changes involving 3q27 in non-Hodgkin's lymphomas with BCL6/LAZ3 rearrangement. 852 78

The BCL-6 gene encoding a nuclear-located Kruppel-type zinc finger protein is rearranged in about 30% diffuse large B-cell lymphomas and is expressed predominantly in normal germinal center B cells and related lymphomas. These findings suggest that BCL-6 may play a role in regulating differentiation of normal germinal center B cells and that its deregulated expression caused by rearrangements may contribute to lymphomagenesis. This prompted us to investigate the expression of the BCL-6 protein in Hodgkin's disease (HD), focusing on the nodular lymphocyte predominance subtype (NLPHD), which differs from classical HD by virtue of the B-cell nature of the malignant cell population (so-called L&H cells) and its relationship with germinal centers. Forty-one HD samples (19 NLPHD, 12 nodular sclerosis, and 10 mixed cellularity) were immunostained with the monoclonal antibodies PG-B6 and PG-B6p that react with a fixative-sensitive and a formalin-resistant epitope on the aminoterminal region of the BCL-6 gene product, respectively. Strong nuclear positivity for the BCL-6 protein was detected in tumor (L&H) cells in all cases of NLPHD. In contrast, BCL-6 was expressed only in a small percentage of Hodgkin and Reed-Sternberg cells in about 30% of classical HD cases. Notably, the nuclei of reactive CD3+/CD4+ T cells nearby to and rosetting around L&H cells in NLPHD were also strongly BCL-6+, but lacked CD40 ligand (CD40L) expression. This staining pattern clearly differed from that of classical HD, whose cellular background was made up of CD3+/CD4+ T cells showing the BCL-6-/CD40L+ phenotype. These results further support the concept that NLPHD is an histogenetically distinct, B-cell-derived subtype of HD and suggest a role for BCL-6 in its development.
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PMID:Distinctive expression pattern of the BCL-6 protein in nodular lymphocyte predominance Hodgkin's disease. 855 67

Despite a common origin from mature lymphoid cells, non-Hodgkin lymphomas (NHL) represent a surprisingly heterogeneous group of lymphoid malignancies whose classification is continuously being remodeled. The most recent proposal, the Revised European-American classification, introduces pathogenetic features among the classification criteria. In this respect, knowledge of the molecular pathogenesis of NHL, which is based upon genetic lesions leading to activation of proto-oncogenes (e.g. BCL-1, BCL-2, BCL-6, c-MYC) or disruption of tumor suppressor genes (e.g. p53), is becoming increasingly relevant for the clinician. These lesions combine into multiple molecular pathways which are selectively associated with distinct NHL types. Thus, for example, rearrangements of BCL-1, BCL-2, BCL-6, and c-MYC ar the genetic hallmarks of mantle cell, follicular, diffuse large cell, and Burkitt's lymphoma, respectively. Overall, from clinical perspective, NHL genetic lesions serve three purposes: a) they assist and complement histologic diagnosis; b) they provide a molecular marker with prognostic relevance; c) they allow evaluation of minimal residual disease through highly specific and highly sensitive technologies.
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PMID:Molecular pathogenesis of non-Hodgkin lymphoma: a clinical perspective. 856 91


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