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)

The majority of non-Hodgkin's B-cell lymphomas contain a t(14;18) translocation that places the bc12 gene into juxtaposition with the transcriptically active Ig heavy-chain locus, thus deregulating the expression of this proto-oncogene. The bc12 gene product is a membrane-associated mitochondrial protein that regulates cell survival through unknown mechanisms. Although overproduction of the normal protein appears sufficient for conferring a selective growth or survival advantage to B cells, point mutations that alter the coding region of translocated bc12 genes have been described previously by others in a lymphoma cell line. However, it is not known whether somatic mutations that alter BCL2 proteins occur in vivo or whether they result from chemotherapy or arise through other mechanisms. For these reasons, we obtained DNA from the t(14;18)-containing tumors of five patients who had not undergone treatment for their disease, and used a polymerase chain reaction (PCR)-mismatch technique for rapid identification of point mutations in a portion of the bc12 open reading frame (ORF) corresponding to the first 131 aminoacids (aa) of the 239 aa p26 BCL2 protein. DNAs from two t(14;18)-containing cell lines were also analyzed. Point mutations in this region of the bc12 gene ORF were detected in three of five patients' tumors and in both cell lines. PCR-mismatch analysis of bc12 in cell lines and non-Hodgkin's lymphoma cases that lacked the t(14;18) translocation was negative, thus establishing the specificity of these results. DNA sequencing determined that these mutations are predicted to produce aa substitutions in the BCL2 proteins of two of the primary tumors and one of the cell lines. Interestingly, two of the patients contained an identical C----T transition that resulted in a nonconservative aa substitution (proline----serine) at position 59 of the BCL2 protein. Further analysis excluded the possibility that these mutations represented hereditary polymorphisms or PCR artifacts. A cluster of four point mutations within the translocation + bc12 allele of one patient had hallmarks of the somatic hypermutation mechanism that is associated with Ig genes and that contributes to antibody diversity. Because of the region of the bcl2 gene analyzed in these t(14;18) translocations is located nearly 300 kbp from the Ig heavy-chain locus, our data suggest that the Ig gene somatic hypermutation mechanism can act over extreme distances of DNA. It remains to be established whether these somatic mutations that alter BCL2 proteins influence the pathobiology of nonHodgkin's lymphomas.
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PMID:Frequent incidence of somatic mutations in translocated BCL2 oncogenes of non-Hodgkin's lymphomas. 133 99

Correlations between cytogenetics, histology, and clinical course continue to emerge in studies of non-Hodgkin's lymphomas. The previously recognized association between the t(14;18) chromosomal translocation and follicular lymphoma has been confirmed; abnormalities of chromosome 3 have correlated specifically with diffuse large cell lymphoma and abnormalities of chromosome 1 have been frequently present in T-cell lymphomas. Rearrangements involving 11q13 (bcl-1) occur most commonly in diffuse lymphocytic lymphoma of intermediate differentiation. Several new recurrent chromosomal abnormalities have also been described. The molecular fine structure of the t(8-14) chromosomal translocation in Burkitt's lymphoma appears to differ between endemic (Epstein-Barr virus-associated) and sporadic cases. In endemic Burkitt's lymphomas, the chromosomal breakpoint is usually far upstream of c-myc oncogene, leaving the regulatory region of the gene intact. In sporadic tumors, a large part of the regulatory region is separated from the gene and transcription is initiated at sites within the first intron. These data raise the possibility that Epstein-Barr virus may contribute to the deregulation of the c-myc gene and that this interaction may be required for tumorigenesis in the presence of some, but not all, types of c-myc damage arising from chromosomal translocations. Partner proteins that oligomerize with c-Myc have been identified in humans and mice (Max and Myn). The partners share with c-Myc the DNA-binding and coiled-coil motifs that are recognized in many other proteins and that function as transcriptional regulators. The Bcl-2 protein has been shown to be a mitochondrial inner membrane protein that blocks programmed cell death (apoptosis). Viral expression has been demonstrated in Epstein-Barr virus-associated Hodgkin's disease, and the spectrum of Epstein-Barr virus-associated lymphoproliferative disease has been expanded to include some T-cell malignancies. A new human herpesvirus has been associated with some cases of Hodgkin's disease.
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PMID:Biology of the lymphomas: cytogenetics, molecular biology, and virology. 166 Nov 67

The bcl2 protooncogene was originally discovered because of its involvement in t(14;18) chromosomal translocations frequently found in non-Hodgkin's lymphomas. The expression of this gene is reported to be highly tissue specific, with bcl2 mRNAs being readily detectable only in hematolymphoid tissues and brain. To explore the possible involvement of bcl2 in neural tumors, we surveyed a variety of tumor cell lines for the presence of the p26-BCL2 protein by immunoprecipitation and immunoblotting methods. Very high levels of BCL2 protein were found in three of nine neuroblastoma (NB) cell lines examined; these levels of p26-BCL2 were comparable to lymphoma cell lines that contain a t(14;18). Despite the impressive relative amounts of BCL2 protein, however, no structural alterations or changes in the methylation status of bcl2 genes were detected in these NB cell lines by conventional Southern blotting. Of the other NB cell lines surveyed, three contained intermediate levels of BCL2 and another three cell lines had little or no detectable BCL2 protein, raising the possibility that determination of relative levels of BCL2 protein may help to segregate neuroblastomas into groups with different biological and clinical characteristics. BCL2 protein levels were not influenced by induction of neuronal differentiation with nerve growth factor in two of the two cell lines examined [SH-SY5Y (high BCL2); GICAN (low BCL2)] and did not correlate with N-MYC gene amplification or expression of nerve growth factor receptors. NB cell lines that contained little or no detectable BCL2 protein, however, tended to contain significant proportions of flat epithelioid cells, whereas bcl2-expressing cell lines were composed primarily of neuronal-like cells, suggesting that expression of this protooncogene correlates with the differentiation characteristics of these tumor cell lines. In addition to NBs, lower levels of BCL2 protein were also found in a variety of other neural crest-derived tumors and tumor cell lines, including some neuroepitheliomas, Ewing's sarcomas, neurofibromas, and melanomas. With regard to tumors of central nervous system origin, bcl2 expression was absent from most medulloblastomas but was detected at moderate to low levels in a retinoblastoma and some glioblastoma multiforme cell lines. Taken together, these findings imply that bcl2 protooncogene expression is differentially regulated within the various lineages of cells that give rise to the nervous system.
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PMID:Differential expression of bcl2 protooncogene in neuroblastoma and other human tumor cell lines of neural origin. 174 26

The t(14;18) translocation, found in most human follicular non-Hodgkin's lymphomas (NHLs), juxtaposes the Bcl-2 oncogene at 18q21 with the immunoglobulin heavy chain locus at 14q32. As a result, the Bcl-2 protein is markedly overproduced. Most of the breakpoints on chromosome 18 cluster at one of two sites, the major breakpoint region (mbr) and the minor cluster region (mcr). Recently, others used the polymerase chain reaction (PCR) to detect the t(14;18) mbr in 32% of specimens diagnosed as Hodgkin's disease (HD). In an attempt to confirm and extend those observations the authors used PCR to assay for both the mbr and mcr in HD specimens diagnosed at their institution and examined the specimens for Bcl-2 overproduction. The authors subjected the DNAs from 28 well-characterized HD tumors of 26 patients to PCR analyses using primers specific for the t(14;18) mbr and mcr breakpoints. Based on various PCR controls, the authors ascertained that 26 of the 28 specimens contained amplifiable template DNA. Southern blotting of the amplification products showed that none of the 26 HD DNAs had detectable t(14;18) mbr or mcr breakpoints. By admixing small amounts of t(14;18)-bearing NHL DNA with HD DNA samples, the authors directly demonstrated that the sensitivity of the PCR assays was adequate for the molecular detection of t(14;18)-bearing cells at a frequency comparable to that of Reed-Sternberg cells and their variants in HD. Immunohistochemical studies employing a highly specific anti-Bcl-2 antiserum under conditions optimized to detect t(14;18)-mediated overexpression of the Bcl-2 gene showed that the Reed-Sternberg cells and variants in all 19 HD tumors examined were negative for Bcl-2 immunostaining. In conclusion, the PCR and immunohistochemical data provided evidence that the t(14;18) translocation was not involved in the pathogenesis of the HD cases.
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PMID:Absence of t(14;18) major and minor breakpoints and of Bcl-2 protein overproduction in Reed-Sternberg cells of Hodgkin's disease. 175 May

The Bcl-2 proto-oncogene was discovered at the t(14;18) breakpoint found in most follicular B-cell lymphomas and some diffuse large-cell lymphomas. Bcl-2 is unique among proto-oncogenes, being localized to mitochondria and extending cell survival by blocking programmed cell death. We examined Bcl-2 protein expression in 82 hematologic malignancies and reactive lymphoid processes. All lymphomas with Bcl-2 rearrangement demonstrated high levels of Bcl-2 protein. However, most follicular and diffuse lymphomas without Bcl-2 rearrangement also displayed intense Bcl-2 staining. In these cases, mechanisms other than classic translocation may be deregulation Bcl-2. The pattern of Bcl-2 staining in follicular lymphoma is the inverse of the pattern in reactive hyperplasia, confirming a role for Bcl-2 immunolocalization in routine diagnosis. Small lymphocytic malignancies, including small lymphocytic lymphoma, mantle zone lymphoma, and chronic lymphocytic leukemia, expressed intermediate levels of Bcl-2. Bcl-2 protein varied in plasma cell dyscrasias. Bcl-2 protein levels in T-cell lymphomas reflected their corresponding stage of development. No substantial Bcl-2 was present in the Reed-Sternberg cells of nodular sclerosing Hodgkin's disease. Chronic myelogenous leukemia was strongly positive for Bcl-2, consistent with the presence of Bcl-2 in normal myeloid progenitors. Immunohistochemistry identified an expanded spectrum of hematopoietic neoplasms in which Bcl-2 may provide a cell survival advantage.
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PMID:Immunolocalization of the Bcl-2 protein within hematopoietic neoplasms. 186 40

The expression of the proto-oncogene bcl-2 was examined in a panel of 75 continuous human leukemia-lymphoma cell lines originated from different hematopoietic cell types. The presence of the bcl-2 protein, as evidenced by Western blotting, and its mRNA, as determined by Northern blotting, were not restricted to cells with the chromosomal translocation t(14;18)(q32;q21), but were also detected in a large number of cell lines without t(14;18). The amount of the bcl-2 protein and mRNA in the cell lines with t(14;18) was in the same order of magnitude as in other bcl-2 expressing cell lines of the same lineage, but without the translocation. Bcl-2 was found in all types of hematopoietic cell lines which were assigned to the following lineages based on their phenotypical characteristics: pre-B, B, plasma, T, myeloid, monocytic, erythroid-megakaryocytic and Hodgkin's lymphoma derived cell lines. The levels of accumulated mRNA and protein corresponded fairly well in most of the cell lines examined. Our results suggest the notion that bcl-2 expression is widely present in hematopoietic cell lines without restriction to single lineages and, in fact, clearly independent of the chromosomal aberration t(14;18). It is conceivable that bcl-2 expression is a common feature in established hematopoietic cell lines and may contribute to their unlimited growth in vitro.
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PMID:Expression of bcl-2 mRNA and protein in leukemia-lymphoma cell lines. 747 72

The distribution of Bcl-2 oncoprotein was studied immunohistochemically in formaldehyde-fixed and paraffin-embedded reactive and neoplastic lymphoid tissue. The potential of Bcl-2 for the differential diagnosis of follicular lesions was emphasized, and the results on follicular lesions were correlated with those of polymerase chain reaction (PCR) assay of the immunoglobulin heavy chain gene rearrangement. In hyperplastic lymphoid tissue, Bcl-2 reactivity was widespread, including germinal center surroundings, scattered cells within the germinal centers, and the T-cell areas in general. Distinctively negative lymphoid populations included the majority of germinal center cells, and the negative staining pattern was maintained in cases of florid hyperplasia. In contrast, follicular lymphoma cells were consistently Bcl-2 positive. The immunohistochemical Bcl-2 reactivity of lymphoma follicles correlated with the clonal PCR amplification pattern of the immunoglobulin heavy chain gene; all Bcl-2-negative hyperplasias revealed a non-clonal pattern. Clusters of monocytoid B cells were Bcl-2 negative, whereas monocytoid B-cell lymphomas and closely related MALT lymphomas were positive. All other small cell non-Hodgkin's lymphomas of B-cell types showed nearly uniform Bcl-2 reactivity, whereas large cell B-cell lymphomas were variably positive (74%). In Hodgkin's cells, Bcl-2 reactivity was seen in the neoplastic populations of most cases of nodular sclerosis and mixed cellularity types, whereas the L&H and Reed-Sternberg cells in lymphocyte predominance Hodgkin's disease were negative in most cases. Bcl-2 immunohistochemistry thus appears very valuable in the differential diagnosis of follicular hyperplasia and neoplasia, and it may help to distinguish between reactive and neoplastic monocytoid B cells. However, Bcl-2 immunohistochemistry is not useful in the subtyping of B-cell lymphomas.
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PMID:Bcl-2 oncoprotein is widespread in lymphoid tissue and lymphomas but its differential expression in benign versus malignant follicles and monocytoid B-cell proliferations is of diagnostic value. 748 87

Discordant morphology between lymph node or extra-nodal site and bone marrow (BM) involvement by non-Hodgkin's malignant lymphoma (NHL) is a common occurrence, causing diagnostic difficulties. Additional diagnostic problems are posed by lymphoid aggregates commonly found in the BM of elderly patients, the age group with the highest incidence of lymphoma. Morphologic features are used to distinguish between benign and malignant lesions but no feature is diagnostic and exceptions are numerous. Immunophenotyping is helpful for detecting B cell monoclonality, but it cannot detect T cell monoclonality. Unique B and T cell gene rearrangement patterns, the molecular "signature" of the lymphoma, can be used to detect monoclonal lymphoid populations. Finding the same rearrangement pattern in the BM as in the primary mass is proof of BM involvement by the same clone of malignant cells. We used B/T and Bcl-2 gene rearrangements to help diagnose cases with discordant morphology between primary site and BM. One hundred and seventy-five specimens, obtained from patients undergoing staging or restaging for NHL, were analyzed for B/T cell and Bcl-2 gene rearrangements by multiple restriction endonuclease digestion and Southern hybridization with 32P labeled JH, JK, CT beta, and Bcl-2 probes. Forty-two specimens (24%) from 24 patients showed discordant morphology: of 13 specimens with atypical lymphoid aggregates, only one had B cell gene rearrangement; of 15 specimens with morphologically benign lymphoid aggregates, one demonstrated B cell gene rearrangement; and of 14 specimens positive for NHL with different morphology than the lymph node, 13 were positive for B cell gene rearrangements. Molecular analysis can aid in the diagnosis of NHL, can establish a "baseline" for detection of recurrence, and is useful in monitoring therapy. These data suggest that it is also a tool for the pathologist in cases of discordant morphology between the primary tumor and BM, and should be strongly considered for each site.
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PMID:Discordant morphologic features in bone marrow involvement by malignant lymphomas: use of gene rearrangement patterns for diagnosis. 763 75

Low-grade follicular non-Hodgkin's lymphomas are characterized by the presence of a t(14;18) chromosomal translocation that results in deregulation of the B-cell lymphoma (Bcl-2) gene. Studies in cell lines and transgenic animal models have suggested that this results in the suppression of apoptotic cell death in germinal centers. B lymphocytes from normal germinal centers and lymph nodes infiltrated by follicular lymphoma were isolated by immunomagnetic depletion of cells bearing CD4, CD8, or slgD for study in vitro. Follicular lymphoma cells expressing Bcl-2 protein were shown to resist apoptosis after isolation, and could be induced to proliferate in a culture system previously described for the growth of normal B lymphocytes. By the use of a mouse fibroblast monolayer transfected with the CDw32 Fc receptor to present CD40 monoclonal antibody in the presence of interleukin-4, prolonged culture was possible. Karyotypic analysis of cultured lymphoma cells showed the t(14;18) translocation, with clonal identity confirmed by polymerase chain reaction amplification of the breakpoints and direct sequence analysis. These findings support the hypothesis that resistance to apoptosis is an influence on the initiation of follicular lymphoma, and provide a novel means of studying in vitro the intercellular reactions that may be important in progression of the disease.
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PMID:Isolated follicular lymphoma cells are resistant to apoptosis and can be grown in vitro in the CD40/stromal cell system. 769 Dec 40

The presence of Epstein-Barr virus (EBV) correlates with some cases of Hodgkin's disease (HD), and its latent membrane protein (LMP) has oncogenic potential by inducing expression of bcl-2 protein. Bcl-2 confers a longer half-life to the cell, which overexpresses it. As the translocation t(14,18), which is most often found in follicular lymphomas, and leads to overexpression of bcl-2, has also been reported in HD, it is possible that there is a correlation between these events in this entity. We stained immunohistochemically 40 cases of HD for the presence of bcl-2 and EBV-LMP. Bcl-2 positivity within reactive lymphocytes was revealed in 29 cases. In five of these cases a week, positive reaction in cytoplasm of Reed-Sternberg cells was observed (one mixed cellularity and four nodular sclerosis cases). The EBV-LMP immunopositivity was observed in 16 of these 29 cases (ten MC and six NS cases). The simultaneous presence of bcl-2 protein and EBV-LMP was found in two cases, the remaining three bcl-2-positive cases did not have EBV-LMP. These results do not support the hypothesis of the correlation between the expression of bcl-2 protein and the presence of EBV-LMP in the pathogenesis of HD as the LMP-dependent stimulation of bcl-2 oncogene.
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PMID:Expression of bcl-2 protein and Epstein-Barr virus latent membrane protein in Hodgkin's disease. 769 30


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