Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors investigated 25 benign lymph nodes in patients infected with the human immunodeficiency virus (HIV) by in situ hybridization (ISH) and immunohistochemistry (IHC) to detect and characterize the Epstein-Barr virus (EBV)-infected cells. After ISH, 22 lymph nodes were found to contain various numbers of Epstein-Barr-encoded RNA (EBER)-positive cells. Most of these cells were B cells. In six lymph nodes with numerous EBV-infected cells, EBNA2-positive/LMP1-positive lymphoblastoid cells were detected by IHC. Exceptional cells (in two specimens) were positively labeled with antigen-Z Epstein-Barr replicative activator (ZEBRA) antibody or BamHI Left Frame 1/Not I (BHLF1/Not I) probes, indicating that EBV replication is not enhanced in the lymphocytes. In normal conditions (healthy individuals), small lymphocytes that express a restricted pattern of viral genes do escape immune response, whereas lymphoblastoid cells do not. Thus, impaired immune system may account for the late proliferation of lymphoblastoid cells (Epstein-Barr nuclear antigen [EBNA]2positive/latent membrane protein [LMP]1 positive) in HIV-infected patients, and could explain why EBV-driven, acquired immunodeficiency syndrome (AIDS)-related, non-Hodgkin's lymphoma occur more frequently in patients with low CD4-positive T cells.
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PMID:Characterization of Epstein-Barr virus-infected cells in benign lymphadenopathy of patients seropositive for human immunodeficiency virus. 860 41

CD40 signalings play crucial roles in B-cell function. To identify molecules which transduce CD40 signalings, we have utilized the yeast two-hybrid system to clone cDNAs encoding proteins that bind the cytoplasmic tail of CD40. A cDNA encoding a putative signal transducer, designated TRAF6, has been molecularly cloned. TRAF6 has a tumor necrosis factor receptor (TNFR)-associated factor (TRAF) domain in its carboxyl terminus and has a RING finger domain, a cluster of zinc fingers and a coiled-coil domain, which are also present in other TRAF family proteins. TRAF6 does not associate with the cytoplasmic tails of TNFR2, CD30, lymphotoxin-beta receptor, and LMP1 of Epstein-Barr virus. Deletion analysis showed that residues 246-269 of CD40 which are required for its association with TRAF2, TRAF3, and TRAF5 are dispensable for its interaction with TRAF6, whereas residues 230-245 were required. Overexpression of TRAF6 activates transcription factor NFkappaB, and its TRAF-C domain suppresses NFkappaB activation triggered by CD40 lacking residues 246-277. These results suggest that TRAF6 could mediate the CD40 signal that is transduced by the amino-terminal domain (230-245) of the CD40 cytoplasmic region and appears to be independent of other known TRAF family proteins.
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PMID:Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. 891 May 14

The tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) is a member of the recently defined TRAF family. It takes part in the signal transduction of the TNF receptor 2 (TNFR2), the lymphotoxin-beta receptor (LT-betaR), CD40, CD30, and LMP1; is induced by LMP1 in vitro; and protects lymphoid cells from apoptosis. To identify the cells in which TRAF1 is active in vivo, we studied TRAF1 transcripts in normal lymphoid tissue, in Epstein-Barr virus (EBV)-induced lymphoproliferations, and in malignant lymphomas with special reference to those that overexpress the cytokine receptor CD30 and CD40 of the TNF receptor family at the single-cell level using a radioactive in situ hybridization. In normal lymphoid tissue, TRAF1 message proved to be absent from all resting B and T cells as well as from macrophages and accessory cells (follicular dendritic cells and interdigitating cells) and present in few perifollicular and intrafollicular lymphoid blasts. In contrast, there was a high and consistent TRAF1 overexpression in EBV-induced lymphoproliferations and Hodgkin's disease. Nearly all non-Hodgkin's lymphoma show low or no TRAF1 expression. Only some cases of diffuse large B-cell lymphoma showed a moderate to high TRAF1 signal. Several of the latter cases were EBV+. These data confirm that TRAF1 is an inducible molecule and indicates its deregulation in the mentioned disorders with the potential of a blockage of the apoptotic pathway.
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PMID:Tumor necrosis factor receptor-associated factor 1 is overexpressed in Reed-Sternberg cells of Hodgkin's disease and Epstein-Barr virus-transformed lymphoid cells. 988 24

Fludarabine is effective in chronic lymphocytic leukaemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). A major side-effect of this purine analogue is immunosuppression which may favour opportunistic infections. Additionally, impairment of immunosurveillance might promote Epstein-Barr virus (EBV) reactivation and possibly favour transformation to high-grade malignancy. The aim of this study was to evaluate the immunosuppression-related effects of the fludarabine-based combination Flucyd in advanced low-grade NHL or CLL by serially monitoring T-lymphocyte subsets, opportunistic infections, EBV-reactivation, and histologic transformation. 24 patients with advanced NHL (n = 21) or CLL (n = 3) received fludarabine 25 mg/m2/d + cyclophosphamide 350 mg/m2/d + dexamethasone 20 mg/d in 3 d courses for a maximum of six courses. The overall response rate was 79% (eight CR, 11 PR, five failures); 11 patients relapsed or progressed between 3 and 19 months from response, and eight are in CR or PR at 3-27 months. The CD4+ lymphocyte counts decreased significantly during therapy from a median of 484/microliter pre-treatment (range 142-1865) to a median of 198/microliter (71-367). In 19 responders monitored off therapy every 3 months until relapse/progression, CD4+ counts were persistently low with minimal recovery over time. During treatment, 16 infections occurred in 11/24 patients. No delayed opportunistic infections occurred in responders while off therapy. The circulating EBV DNA load serially measured in 19 patients by a quantitative PCR assay showed an increase in four patients during treatment. A lymph node biopsy performed in two of these was PCR positive for EBV DNA, whereas LMP1 and EBERs were negative. Six NHL patients evolved into high-grade B-cell NHL. In conclusion, fludarabine combined with cyclophosphamide and dexamethasone is an effective therapy for recurrent indolent lymphoma. This combination produces prolonged T-lymphocytopenia and has the potential to reactivate a latent EBV infection. T-cell dysfunction, however, is not associated with higher incidence of clinical opportunistic infections and does not adversely influence clinical outcome.
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PMID:The immunosuppression and potential for EBV reactivation of fludarabine combined with cyclophosphamide and dexamethasone in patients with lymphoproliferative disorders. 1060 97

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis, and it may also be found in a wide variety of benign and malignant lesions including oral hairy leukoplakia, inflammatory pseudotumor, Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. Molecular testing is increasingly important in the diagnosis and monitoring of patients affected by these diseases. In biopsy tissues, molecular detection of EBV-encoded RNA transcripts by in situ hybridization remains the gold standard for proving that a histopathological lesion is EBV-related. EBV-encoded RNA hybridization and EBV LMP1 immunostains are used routinely to detect latent EBV in tissues affected by posttransplant lymphoproliferative disorder (PTLD) or in enlarged nodes from patients with infectious mononucleosis. Traditional serology is the best test for evaluating acute versus remote infection in healthy individuals. High serological titers serve as a tumor marker for some EBV-related malignancies, but titers are not a dependable tumor marker in immunocompromised hosts. EBV viral load testing by quantitative DNA amplification of blood samples is a promising new laboratory test that has proven useful for early diagnosis and monitoring patients with PTLD. Recent studies suggest a role for EBV viral load testing in nasopharyngeal carcinoma, Hodgkin's disease, and AIDS patients with brain lymphoma. Further research is needed to define more fully the clinical utility of viral load tests in the full spectrum of EBV-associated diseases. Gene expression profiling is on the horizon as a means to improve subclassification of EBV-related diseases and to predict response to therapy.
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PMID:Molecular diagnosis of Epstein-Barr virus-related diseases. 1122 65

Epstein-Barr virus (EBV) is associated with several lymphoid and epithelial human malignancies. The latter include gastric adenocarcinomas, while sporadic colorectal adenocarcinomas (CRCs) have been reported to be EBV-negative. Recently, increased numbers of EBV-infected B lymphocytes have been detected in intestinal mucosal samples affected by ulcerative colitis (UC) and, to a lesser extent, Crohn's disease (CD). Both CRC and colorectal non-Hodgkin's lymphoma (NHL) are recognized complications of inflammatory bowel disease (IBD), but it is unclear to what extent EBV contributes to the development of these neoplasms. Seventeen cases of IBD-associated CRC and nine cases of IBD-associated colorectal NHL were therefore studied for the presence of EBV by in situ hybridization. EBV-positive cases were further studied for the expression of the EBV-encoded nuclear antigen (EBNA) 2 and the latent membrane protein (LMP) 1 of EBV by immunohistochemistry. Four out of seven cases of colorectal NHL associated with UC were shown to be EBV-positive. In addition, two of two colorectal NHLs developing in patients with CD were EBV-positive. Of the EBV-positive lymphomas, three displayed a pattern of EBV latent gene expression consistent with type I latency (EBNA2(-)/LMP1(-)), two a type II pattern (EBNA2(-)/LMP1(+)), and one a type III pattern (EBNA2(+)/LMP1(+)). These findings suggest that EBV infection is involved in the pathogenesis of a proportion of colorectal NHLs developing in IBD. Iatrogenic immunosuppression may contribute to the development of these lymphomas. By contrast, all 17 IBD-associated CRCs were EBV-negative, including a case of CRC occurring synchronously with an EBV-positive NHL. In conjunction with previous reports on sporadic CRCs, this suggests that EBV is not involved in the pathogenesis of CRC.
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PMID:Epstein-Barr virus infection in colorectal neoplasms associated with inflammatory bowel disease: detection of the virus in lymphomas but not in adenocarcinomas. 1451 49

The samples of tumor biopsy, blood, and saliva from 10 patients with Hodgkin's disease, 10 patients with non-Hodgkin's lymphoma, and the blood samples of 20 donors were tested by polymerase chain reaction (PCR) for standard (wild) B95-8 and Cao-like (deleted) variants of the LMP1 gene. The paraffin sections of most PCR-tested tumors were also investigated by immunohistochemistry using the monoclonal antibodies S12 or 7D7 to detect the expression of the standard or Cao-like variants of LMP1 protein, respectively. It is suggested that Eptein-Barr virus (EBV) that contains the above deletion is not crucial for the development of the study lymphoproliferative malignancies. The fact that in some cases there is the Cao-like variant of LMP1 in the tumor biopsy specimen and its standard variant LMP1-B95-8 in the biological fluids of the same patient is very likely to suggest that the patient is infected with both types of the virus or there is genetic mutation(s) of EBV during viral carcinogenesis preceding or accompanying the development of a tumor.
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PMID:[LMP1 gene variants of Epstein-Barr virus in patients with some lymphoproliferative malignancies]. 1675 77

Bortezomib, an inhibitor of the 26S proteasome, is currently approved for treatment of multiple myeloma and is being studied for therapy of non-Hodgkin's lymphoma. We found that Epstein-Barr virus (EBV)-positive B cells with type III latency were more susceptible to killing by bortezomib than those with type I latency. Bortezomib induced apoptosis of EBV lymphoblastoid cell lines (LCLs) by inducing cleavage of caspases 8 and 9; apoptosis was inhibited by pretreatment with a pan-caspase inhibitor. Bortezomib reduced the levels of the p50 and p65 components of the canonical NF-kappaB pathway and reduced the level of p52 in the noncanonical NF-kappaB pathway, which is induced by EBV LMP1. Bortezomib inhibited expression of cIAP-1, cIAP-2, and XIAP, which are regulated by NF-kappaB and function as inhibitors of apoptosis. Bortezomib did not inhibit expression of several other antiapoptotic proteins, including Bcl-2 and Bcl-XL. Finally, bortezomib significantly prolonged the survival of severe combined immunodeficiency mice inoculated with LCLs. These findings suggest that bortezomib may represent a novel strategy for the treatment of certain EBV-associated lymphomas.
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PMID:Bortezomib induces apoptosis of Epstein-Barr virus (EBV)-transformed B cells and prolongs survival of mice inoculated with EBV-transformed B cells. 1762 72

TNF-receptor-associated factors (TRAFs) are intracellular proteins that bind to the cytoplasmic portion of TNF receptors and mediate downstream signaling. The six known TRAF proteins play overlapping yet distinct roles in controlling immune responses as well as cellular processes such as activation of NF-kappaB and JNK signaling pathways. For example, CD40 binds to TRAF2, TRAF3 and TRAF6 to control B cell differentiation, proliferation and growth. In contrast, binding of lymphotoxin-beta receptor (LTbetaR) to TRAF2 and TRAF5 propagates signals leading to activation of NF-kappaB, while binding to TRAF3 induces negative regulation of this pathway and leads to apoptosis in tumor cells. Binding recognition is mediated by specific contacts of a consensus recognition sequence in the partner with residues in a hydrophobic crevice on the TRAF molecule. Since each of these protein-protein interactions occurs within this same binding crevice, it appears that TRAF-mediated cellular mechanisms may be regulated, in part, by the level of expression or recruitment of the adaptor proteins or receptors that are competing for the crevice. The specific contacts of CD40, LTbetaR and BAFF-R have been defined in crystal structures of the complex with TRAF3. In addition, the downstream regulator TANK and the viral oncogenic protein LMP1 from the Epstein Barr virus also bind to the same TRAF crevice and these contacts have also been described crystallographically. Comparison of these five crystal structures has revealed that the recognition motifs in each of these proteins are accommodated in one TRAF3 binding crevice and that the binding interface is structurally and functionally adaptive. In this chapter, the molecular details of the interactions will be described and correlated with the functional implications for multiple TRAF3 roles in cellular regulation.
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PMID:Protein-protein interactions in TRAF3. 1763 21

T-cell non-Hodgkin's lymphomas (NHLs) represent 10% to 15% of all diagnosed lymphomas in Western countries. Various geographic frequencies of T-cell NHL have been documented, in part reflecting increased exposure to pathogenic factors such as Epstein-Barr virus (EBV). Our aims were to assess EBV and p53 expression in Argentine pediatric T-cell lymphoma and to correlate them with patients' survival. Epstein-Barr encoded RNAs (EBERs) in situ hybridization and LMP1 and p53 immunohistochemical staining were performed on formalin-fixed paraffin-embedded lymph node biopsies from 25 pediatric T-lymphoma patients. In 17 of 25 samples good-quality DNA was obtained, and EBER polymerase chain reaction was assessed to confirm in situ hybridization and immunohistochemical results. Epstein-Barr virus expression was found in 8.0% of cases. p53-positive staining was distributed in 92% of pediatric cases. Kaplan-Meier survival analysis showed that neither EBV nor p53 expression was statistically significantly associated with event-free survival. Our data showed a low frequency of EBV association with pediatric T-cell lymphoma. It seems that p53 plays an important role in proliferation in our studied population, since it is overexpressed in 92% of T-cell lymphoma cases.
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PMID:Low frequency of Epstein Barr virus association and high frequency of p53 overexpression in an Argentinean pediatric T-cell lymphoma series. 1854 Jun 92


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