Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-Hodgkin's (NHL) B cell lymphomas are growth-inhibited by ligation of their CD40 molecules. This inhibition is not absolute in that approximately 50% of the cells are not inhibited. We conducted studies to see if other signals that have been reported to inhibit B cell lymphoma growth could be used in combination with anti-CD40 signaling to completely inhibit growth. Ligation of surface immunoglobulin (Ig), CD19, CD20, CD37 or CD95 with soluble antibody did not affect growth of the panel of NHL cells examined. Ligation of CD20, CD19 or CD95 was inhibitory for some NHL cell lines if the primary antibody was crosslinked with a secondary antibody. Combining anti-CD40 with anti-CD19, anti-CD20, or anti-Ig resulted in increased inhibition past that produced by anti-CD40 alone. The additive effect of anti-CD40 and other antibodies to selected surface markers was not observed in all NHL cell lines. Crosslinking of CD95 was also growth inhibitory for the majority of the NHL, and when combined with anti-CD40 under conditions that afforded crosslinking of the two receptors, increased inhibition was seen in three of the NHL cell lines. We found that cAMP or sodium butyrate (NaB) were also effective at inhibiting growth of the NHL cells; this was a profound inhibition (approaching 100%) compared to the 50% inhibition seen with anti-CD40 treatment. The potential for anti-CD40 and either cAMP or NaB to be additive was tested and not found to be the case. The ability to inhibit proliferation of the NHL was very dynamic with some antibody combinations being either inhibitory for multiple cells, not having an effect at all, or in some cases being stimulatory. This suggests that the NHL may represent unique stages of B cells that might serve as a model system which could be developed to precisely categorize patient NHL.
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PMID:Increased inhibition of proliferation of human B cell lymphomas following ligation of CD40, and either CD19, CD20, CD95 or surface immunoglobulin. 895 76

Fas (CD95) and its ligand are central regulatory molecules in hematopoietic cells. Previous studies have suggested a role for Fas in the regulation of tumor progression, but Fas has not yet been conclusively identified as a tumor suppressor. Fas-deficient individuals lack malignant tumors, perhaps because of regulation by T cells. To investigate such a possibility, mice deficient in both T cells and Fas were generated, and they were found to develop severe B cell dysregulation characterized by malignant, lethal B cell lymphoma. Lymphoma arose from a monoclonal B220+CD19-CD5-CD23- B cell secreting immunoglobulin M, kappa rheumatoid factor. In contrast, animals containing alpha beta T cells, gamma delta T cells, and/or functional Fas suppressed the development of lymphoma. These data indicate that Fas functions as a tumor suppressor, and identifies roles for both alpha beta T cells and gamma delta T cells in Fas-independent tumor regulation.
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PMID:A tumor-suppressor function for Fas (CD95) revealed in T cell-deficient mice. 906 31

Fas (Apo-1/CD95) ligand (FasL) is a cytotoxic molecule used by T lymphocytes and natural killer cells for target-cell killing and by nonmalignant and malignant cells in the suppression of immune responses. In this study, FasL expression in B- and T-cell non-Hodgkin's lymphomas was investigated by paraffin immunohistochemical analysis. FasL expression was found to be weak in nonaggressive lymphomas (chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, Grade 1 follicular center cell lymphoma) and mantle cell lymphoma but strong in aggressive B-cell lymphomas (diffuse large B-cell lymphoma, Burkitt's-lymphoma). Precursor B-lymphoblastic lymphomas were more heterogeneous, with expression varying from weak to strong. In T-cell lymphomas (anaplastic large-cell lymphoma; peripheral T-cell lymphoma, unspecified), strong FasL expression was observed. Apparently, FasL expression is not limited to neoplasms derived from T cells or natural killer cells, and it might play a supporting role in the progression of non-Hodgkin's lymphomas.
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PMID:Fas ligand expression in nodal non-Hodgkin's lymphoma. 957 88

The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report, we present the histopathological and immunophenotypic features seen in the lymph nodes (n = 16), peripheral blood (n = 10), bone marrow (n = 2), spleen (n = 3), and liver (n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-alphabeta CD3+ CD4-CD8- (double-negative, DN) T cells that were negative for CD45RO. CD45RA+ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by in situ detection of DNA fragmentation and staining with MIB-1, respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA+ T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5+ B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS. Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin's disease, respectively).
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PMID:Pathological findings in human autoimmune lymphoproliferative syndrome. 981 46

Treatment of B cell lymphoma patients with MoAbs specific for the common B cell marker (CD20) has shown a good overall response rate, but the number of complete remissions is still very low. The use of MoAbs coupled to radioisotopes can improve the results, but induces undesirable myelodepression. As an alternative, we proposed to combine the specificity of MoAbs with the immunogenicity of T cell epitopes. We have previously shown that an anti-Ig lambda MoAb coupled to an MHC class II-restricted universal T cell epitope peptide P2 derived from tetanus toxin induces efficient lysis of a human B cell lymphoma by a specific CD4+ T cell line. Here we demonstrate that the antigen presentation properties of the MoAb peptide conjugate are maintained using a MoAb directed against a common B cell marker, CD19, which is known to be co-internalized with the B cell immunoglobulin receptor. In addition, we provide evidence that B cell lysis is mediated by the Fas apoptosis pathway, since Fas (CD95), but not tumour necrosis factor receptor (TNFr) or TNF-related receptors, is expressed by the target B cells, and FasL, but not perforin, is expressed by the effector T cells. These results show that B cell lymphomas can be 'foreignized' by MoAb-peptide P2 conjugates directed against the common B cell marker CD19 and eliminated by peptide P2-specific CD4+ T cells, via the ubiquitous Fas receptor. This approach, which bridges the specificity of passive antibody therapy with an active T cell immune response, may be complementary to and more efficient than the present therapy results with unconjugated chimeric anti-CD20 MoAbs.
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PMID:An anti-CD19 antibody coupled to a tetanus toxin peptide induces efficient Fas ligand (FasL)-mediated cytotoxicity of a transformed human B cell line by specific CD4+ T cells. 982 73

Members of the Bcl-2 gene family have been implicated in the regulation of cell death induced by cytostatic drugs. In some malignancies such as B-cell lymphoma, there is evidence that high expression of Bcl-2 is an independent negative prognostic marker and the overexpression of Bcl-2 has been shown to confer resistance to cytotoxic drugs by preventing drug-induced apoptosis. This function of Bcl-2 can be antagonized by apoptosis-promoting members of the Bcl-2 family. We previously showed that overexpression of Bax restores the chemosensitivity of Bax-deficient breast cancer cell lines. Therefore, we investigated whether the death-promoting Bcl-2 homologue Bik/Nbk can enhance cytostatic drug-induced apoptosis. As a model, we used the T-cell leukemia H9 (CD3(+) and CD4(+)CD8(-)), which is resistant to corticosteroid-induced cell death and does not express endogenous Bik/Nbk. Sensitivity for drug-induced apoptosis was increased 10- to 39-fold in cells transfected with the full-length coding sequence of Bik/Nbk. In addition, apoptosis induced via CD95/Fas or heat shock was increased to a similar extent. These data show that Bik/Nbk, which, unlike Bax, carries only a BH3 but no BH1 or BH2 domain may be a target to enhance chemosensitivity. The complete suppression of tumor growth in a severe combined immunodeficient mouse xenotransplant model suggests that, in analogy to Bax, Bik/Nbk may function as a tumor suppressor gene.
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PMID:Expression of the death gene Bik/Nbk promotes sensitivity to drug-induced apoptosis in corticosteroid-resistant T-cell lymphoma and prevents tumor growth in severe combined immunodeficient mice. 1041 3

Human astrocytomas frequently co-express Fas (APO-1/CD95) and Fas ligand (FasL), yet do not appear to be overly susceptible to suicidal, fratricidal and immune-mediated elimination. This suggests that these gliomas have acquired mechanisms to prevent Fas-mediated apoptosis from occurring. Candidates for such a role include transforming growth factor-beta2 (TGFbeta2) and B-cell lymphoma/leukemia-2 (Bcl-2). TGFbeta2 effectively functions by hiding tumor cells from the immune system. This may potentially prevent the delivery of FasL from cytolytic T cells to Fas bearing astrocytomas. Bcl-2 works by rendering gliomas resistant to Fas-mediated apoptosis. Using immunohistochemistry, we analyzed seventy-six human astrocytomas (11 World Health Organization (WHO) grade I, 17 grade II, 17 grade III, and 31 grade IV) for the expression of Fas, FasL, TGFbeta2 and Bcl-2 in vivo. Positive immunoreactivity was found to significantly increase with increasing tumor grade for Fas (p < 0.0002), FasL (p < 0.0001), TGFbeta2 (p < 0.001) and Bcl-2 (p < 0.01). In addition, Fas/FasL co-expression, a counter-intuitive combination of factors in regards to glioma survival, also increased with WHO grade. Forty-five of 76 (59%) astrocytomas co-expressed Fas and FasL. Of those co-expressing Fas and FasL, 44 of 45 (98%) produced TGFbeta2, and 26 of 45 (58%) expressed Bcl-2. We found a significant positive correlation between Fas/FasL co-expression and TGFbeta2 (p < 0.002) and Bcl-2 (p < 0.005) production. We conclude that Fas and FasL are frequently co-expressed in human astrocytomas and these tumors are likely to produce other immunosuppressive and antiapoptotic factors such as TGFbeta2 and Bcl-2.
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PMID:Human astrocytomas co-expressing Fas and Fas ligand also produce TGFbeta2 and Bcl-2. 1072 Feb

Primary mediastinal B-cell lymphoma is a locally highly aggressive but poorly disseminating tumor composed of medium sized or large cells most probably of thymic medullary origin. It has a mature B-cell phenotype, typically lacks immunoglobulin expression and has variable defects in expression of HLA-molecules. We present here a cell line, MedB-1, derived from such a tumor. As is frequently found in mediastinal B-cell lymphomas in situ, MedB-1 is CD10(-), CD19(+), CD21(-), CD22(+), CD23(+), CD25(-), CD37(+), CD38(-), CD39(+), CD40(+), CD54(+), CD95(+). Like the parental tumor, MedB-1 lacks HLA-A,B,C alpha-chains and beta(2)microglobulin and expresses HLA-D molecules at decreased levels. Both parental tumor and MedB-1 cells are clonally related as shown by immunoglobulin heavy chain gene rearrangement analysis. Unlike the parental tumor tissue, the MedB-1 cell line cytoplasmically expresses IgG/kappa in a very small subset of cells under standard culture conditions. MedB-1 does not contain any Epstein-Barr virus DNA. In a tissue adhesion assay MedB-1 cells showed an extensive binding to the medullary region of normal thymus. Altogether, MedB-1 is a suitable tool for functional and molecular analysis of this distinct lymphoma entity.
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PMID:MedB-1, a human tumor cell line derived from a primary mediastinal large B-cell lymphoma. 1129 Oct 70

Fas (CD95, APO-1) mutations were found in autoimmune diseases and some lymphomas, suggesting impairment of Fas-mediated cell death signaling that may cause tumor development. Because mucosa-associated lymphoid tissue (MALT)-type lymphoma B cells recognize autoantigens and proliferate in response to antigen and T cell-mediated signals, it is suggestive that autoreactive B cell lymphoma precursor cells may have escaped the Fas-mediated checkpoint that normally operates in healthy individuals. Using different biochemical, molecular, and functional approaches, we analyzed the Fas signaling in malignant B cells from seven MALT-type lymphomas that were additionally characterized for the t(11;18)(q21;q21) and four gastric diffuse large B cell lymphomas (DLBL). All DLBLs and three of seven MALT-type lymphomas were resistant to Fas-mediated apoptosis in vitro. Moreover, four of five MALT-type lymphomas analyzed and one of three DLBLs analyzed showed mutations in Fas mRNA transcripts but no loss of heterozygosity in the Fas promotor region. Alternative mechanisms of resistance to apoptosis, such as decreased expression of Fas or production of soluble Fas were not operative. Therefore, it is suggestive that a subgroup of MALT-type lymphoma B cells, irrespective of t(11;18)(q21;q21), escape the censoring Fas pathway by mutating and inactivating Fas. This identifies a key regulatory step in early MALT-type lymphomagenesis.
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PMID:Loss of Fas (CD95/APO-1) regulatory function is an important step in early MALT-type lymphoma development. 1145 87

The CD95 (Fas) molecule transmits apoptotic signals important in B-cell development and the genesis of B-cell lymphoma. We have investigated the surface and intracellular expression of CD95 in Burkitt's lymphoma (BL) cells, an important non-Hodgkin's lymphoma of B-cell origin. Group I BL cells did not express CD95 at the cell surface, but contained high levels of this receptor in the cytoplasm. In contrast, group III BL cells expressed CD95 intracellularly and at the cell surface. In group I and group III BL cells, cytoplasmic CD95 was localized to the Golgi complex, as assessed by confocal immunofluorescence microscopy and subcellular fractionation followed by immunoblotting. Trafficking through the Golgi complex is regulated by elements within the target protein and cellular sorting mechanisms. CD95 contains candidate signals for interaction with trafficking machinery. Group I BL cells can be induced to upregulate surface expression of CD95 following CD40 ligation and certain group I BL cell lines drift invitro to a group III phenotype, with consequent surface expression of CD95. Taken together, these observations show that CD95 can either be retained in the Golgi complex or exported to the cell surface, and suggest that membrane trafficking has an important and previously unrecognized role in regulating CD95 expression in B lymphocytes.
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PMID:CD95 (Fas) expression is regulated by sequestration in the Golgi complex in B-cell lymphoma. 1213 37


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