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)

Marginal zone B-cell lymphoma (MZBCL) including extranodal mucosa-associated lymphoid tissue (MALT)-type lymphoma, nodal, and splenic MZBCL represents a distinct subtype of B-non-Hodgkin's lymphoma. Recently, important progress in the elucidation of the genetic mechanisms underlying the pathogenesis and disease progression of these lymphomas has been made. The API2 gene, an inhibitor of apoptosis, and the novel MLT gene have been found to be altered by the t(11;18)(q21;21), which represents the most frequent structural chromosomal abnormality in extranodal low-grade MALT lymphoma. Another gene involved in the regulation of apoptosis, the BCL10 gene, has been cloned from a MALT lymphoma cytogenetically characterized by the t(1;14)(p22;q32). Along the same lines, inactivating mutations of the proapoptotic FAS gene have been detected in a relatively high proportion of extranodal MZBCLs. Considering these data and the fact that at least some MALT lymphomas show low levels of apoptosis and seem to escape from FAS-mediated apoptosis one may speculate that abrogation of apoptosis constitutes a central pathogenetic mechanism in the development of these lymphomas. The pathogenetic role of trisomy 3, the most frequent numerical chromosomal change of MZBCL, is not known. The minimal overrepresented region has been delineated to 3q21-23 and 3q25-29 using comparative genomic hybridization. The BCL6 proto-oncogene, located on 3q27, which is rearranged in some MZBCL and a high proportion of large cell B-cell lymphomas with extranodal localization, represents one of the candidate genes residing in these critical regions.
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PMID:Genetic abnormalities in marginal zone B-cell lymphoma. 1079 25

The long median survival time of patients with follicular non-Hodgkin's lymphoma (NHL), means that the efficacy of new treatments are difficult to assess in the short term. Bcl-2 is an inhibitor of apoptosis and overexpression of the bcl-2 gene in the blood or bone marrow is a feature in up to 85% of patients with follicular NHL. Levels of bcl-2(+) cells in the peripheral blood or bone marrow therefore are a useful measure of disease status in such patients and can be detected by polymerase chain reaction (PCR). Complete bcl-2 clearance from the bone marrow (molecular remission) following autologous stem cell transplant (ASCT) for follicular NHL is considered to be an important prognostic factor for disease-free survival. Tumour cell contamination of the stem cell grafts used in ASCT is commonly associated with relapse. This can be addressed by purging the stem cell harvest prior to transplantation. Various methods of in vitro purging after stem cell collection have been shown to reduce the level of contamination but yield is invariably reduced and grafts remain bcl-2 positive. However, in vivo purging with rituximab during the process of collection has been used to obtain bcl-2-negative stem cell harvests without compromising the yield. Rituximab is a monoclonal antibody licensed for treatment of relapsed and refractory low-grade or follicular NHL. Rituximab targets the CD20 antigen, which is found on cells of the B cell lineage. When used for in vivo purging it depletes the peripheral blood of CD20-positive cells and prevents contamination by lymphoma cells. Molecular remission, as measured by bone-marrow bcl-2 clearance, has been achieved in 7/7 patients with follicular NHL at 1 year after treatment with ASCT using rituximab as an 'in vivopurse', followed by rituximab maintenance. Early clinical outcomes are also encouraging.
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PMID:Bcl-2 clearance: optimising outcomes in follicular non-Hodgkin's lymphoma. 1184 Jan 56

The anti-CD20 monoclonal antibody rituximab (Rituxan, IDEC-C2B8) has shown promising results in the clinical treatment of a subset of patients with low grade or follicular non-Hodgkin's lymphoma (NHL). However, chemotherapy- and rituximab-refractory NHL patients may benefit from a regimen in which rituximab acts as a sensitizing agent. This study examined the apoptotic signaling mediated by rituximab on rituximab- and paclitaxel-resistant CD20(+) NHL B cell lines (Ramos, Raji, Daudi, and 2F7). Treatment with either rituximab (20 micro g/ml) or paclitaxel (0.1-1000 nM) inhibited viable cell recovery of NHL lines. Neither rituximab nor paclitaxel induced significant apoptosis, although the combination treatment resulted in synergy in apoptosis. Rituximab selectively down-regulated Bcl-xL and induced apoptosis protease activating factor 1 (Apaf-1) expressions in Ramos cells. Paclitaxel down-regulated the expression of Bcl-xL and inhibitor of apoptosis proteins (c-IAP-1) and up-regulated the expression of Bad and Apaf-1. The combination treatment resulted in the formation of truncated Bid, cytosolic accumulation of cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI, activation of caspase-9, caspase-7, caspase-3, and cleavage of poly(ADP-ribose) polymerase. The findings identify two potential novel intracellular targets of rituximab-mediated signaling in Ramos NHL cells (i.e., Bcl-xL and Apaf-1). Further, the findings show that both rituximab and paclitaxel selectively modify the expression pattern of proteins involved in the apoptosis signal transduction pathway and, through functional complementation, the combination results in synergy in apoptosis. The potential therapeutic significance of these findings is discussed.
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PMID:Rituximab (anti-CD20) selectively modifies Bcl-xL and apoptosis protease activating factor-1 (Apaf-1) expression and sensitizes human non-Hodgkin's lymphoma B cell lines to paclitaxel-induced apoptosis. 1461 92

Survivin is a member of the inhibitor of apoptosis protein (IAP) family and functions both as an apoptosis inhibitor and a regulator of cell division. Survivin overexpression is common in many human tumors and correlates with survival in large cell non-Hodgkin's lymphoma. To evaluate this molecule as a potential therapeutic target in large-cell lymphoma, we evaluated the effect of survivin inhibition both in vitro and in vivo. Using an antisense oligonucleotide (ASO) approach, cell growth was significantly inhibited in the DoHH2, RL and HT lymphoma cell lines. In a lymphoma xenograft model, the development of tumors as well as the growth of established tumors was inhibited in the survivin ASO-treated mice compared to controls. To assess the efficacy of the survivin ASO in combination with other biological agents, we combined the survivin ASO with an anti-CD20 monoclonal antibody, rituximab. The effect of survivin ASO and rituximab in combination was additive in vitro. In vivo, however, suppression of tumor growth with the combination was not significantly superior to controls. We conclude that inhibition of survivin expression is an attractive therapeutic strategy in aggressive non-Hodgkin's lymphomas, and that combining survivin ASO with rituximab may enhance the efficacy of this approach.
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PMID:Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin's lymphoma. 1474 4

TNFSF14/LIGHT is a member of the tumor necrosis factor superfamily that binds to lymphotoxin-beta receptor (LTbetaR) to induce cell death via caspase-dependent and caspase-independent pathways. It has been shown that cellular inhibitor of apoptosis protein-1 inhibits cell death by binding to LTbetaR-TRAF2/TRAF3 complexes and caspases. In this study, we found that both Kaposi's sarcoma-associated herpesvirus K7 (KSHV-K7), a viral inhibitor of apoptosis protein, and the structurally related protein survivin-DeltaEx3 could inhibit LTbetaR-mediated caspase-3 activation. However, only survivin-DeltaEx3 could protect cells from LTbetaR-mediated cell death. The differential protective effects of survivin-DeltaEx3 and KSHV-K7 can be attributed to the fact that survivin-DeltaEx3, but not KSHV-K7, is able to maintain mitochondrial membrane potential and inhibit second mitochondria-derived activator of caspase/DIABLO release. Moreover, survivin-DeltaEx3 is able to inhibit production of reactive oxygen species and can translocate from nucleus to cytosol to associate with apoptosis signal-regulating kinase 1 after activation of LTbetaR. Furthermore, survivin-DeltaEx3 protects LTbetaR-mediated cell death in caspase-3-deficient MCF-7 cells. Thus, survivin-DeltaEx3 is able to regulate both caspase-dependent and caspase-independent pathways, whereas inhibition of caspase-independent pathway is both sufficient and necessary for its protective effect on LTbetaR-mediated cell death.
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PMID:Inhibition of lymphotoxin-beta receptor-mediated cell death by survivin-DeltaEx3. 1654 Jun 54

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive disease in which the human T-cell lymphotropic virus type I (HTLV-I) has been recognized as the etiologic agent. Fludarabine is a purine analog that has demonstrated significant activity in B-cell malignancies, including chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma. This study explored the effects of fludarabine on HTLV-1-infected T cells (MT-1, -2, -4 and HUT102). Fludarabine induced growth arrest and apoptosis of these cells, as measured by 3-(4,5-dimethylithiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, cell cycle analysis and annexin V staining. Moreover, exposure of HTLV-1-infected T cells to fludarabine decreased the levels of X-inhibitor of apoptosis protein in conjunction with inhibition of nuclear factor kappaB (NF-kappaB)/DNA-binding activity, as measured by Western blot analysis and electrophoretic mobility shift and reporter gene assays, respectively. Further studies found that fludarabine accumulated NF-kappaB and inhibitory subunit of NF-kappaB in cytosole in conjunction with downregulation of NF-kappaB in nucleus, suggesting that fludarabine blocked nuclear translocation of NF-kappaB. Taken together, fludarabine may be useful for treatment of individuals with ATL and other types of cancer in which NF-kappaB plays a role.
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PMID:Fludarabine induces apoptosis of human T-cell leukemia virus type 1-infected T cells via inhibition of the nuclear factor-kappaB signal pathway. 1734 17

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL), which is also a significantly heterogeneous disease. Survivin, a unique member of the inhibitor of apoptosis (IAP) family, is overexpressed in various cancers, including some types of lymphoma. It is found that inhibitor of apoptosis protein, survivin, plays an important role in the development and progression of DLBCL. Survivin is able to inhibit the cell apoptosis, and enhances the cell proliferation. Many studies showed that survivin may be considered as an independent unfavorable prognostic index of DLBCL. The poor prognostic cases early are screened in combination of survivin expression with International Prognostic Index (IPI), and improve the outcome of DLBCL. Survivin selectively expressed in tumor tissue, which provide an ideal target for tumor therapy. Modulation of survivin expression or function may provide a novel approach for experimental therapy in patients with DLBCL. In this review, the progress of study on mechanism of survivin protein, the survivin expression in DLBCL, its significance in diagnosis and therapy of DLBCL, and the prospective trend were summarized.
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PMID:[Progress of study on survivin in diffuse large B-cell lymphoma--review]. 1909 70

The lymphotoxin-beta receptor (LTbetaR) activates the NF-kappaB2 transcription factors, p100 and RelB, by regulating the NF-kappaB-inducing kinase (NIK). Constitutive proteosomal degradation of NIK limits NF-kappaB activation in unstimulated cells by the ubiquitin:NIK E3 ligase comprised of subunits TNFR-associated factors (TRAF)3, TRAF2, and cellular inhibitor of apoptosis (cIAP). However, the mechanism releasing NIK from constitutive degradation remains unclear. We found that insertion of a charge-repulsion mutation in the receptor-binding crevice of TRAF3 ablated binding of both LTbetaR and NIK suggesting a common recognition site. A homologous mutation in TRAF2 inhibited cIAP interaction and blocked NIK degradation. Furthermore, the recruitment of TRAF3 and TRAF2 to the ligated LTbetaR competitively displaced NIK from TRAF3. Ligated LTbetaR complexed with TRAF3 and TRAF2 redirected the specificity of the ubiquitin ligase reaction to polyubiquitinate TRAF3 and TRAF2, leading to their proteosomal degradation. Stimulus-dependent degradation of TRAF3 required the RING domain of TRAF2, but not of TRAF3, implicating TRAF2 as a key E3 ligase in TRAF turnover. The combined action of competitive displacement of NIK and TRAF degradation halted NIK turnover, and promoted its association with IKKalpha and signal transmission. These results indicate the LTbetaR modifies the ubiquitin:NIK E3 ligase, and also acts as an allosteric regulator of the ubiquitin:TRAF E3 ligase.
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PMID:Allosteric regulation of the ubiquitin:NIK and ubiquitin:TRAF3 E3 ligases by the lymphotoxin-beta receptor. 2034 96

This study was aimed to explore clinical significance of Livin mRNA and protein expressions in non-Hodgkin's lymphoma (NHL). The immunohistochemistry was used to determine the expression of Livin protein in lymph nodes of 30 patients with NHL and 11 patients with reactive hyperplasia of lymph node. The real-time PCR was performed to detect the expression levels of Livin mRNA in 20 patients with NHL, 10 patients with reactive hyperplasia of lymph node and 4 normal person lymph nodes. The correlation of Livin mRNA and protein expressions with NHL clinical features were analyzed. The results showed that the expression of Livin mRNA was statistically higher in NHL samples than in normal lymph nodes and reactive hyperplastic lymph nodes (12.4 vs 0.34, 12.4 vs 0.61, median) (p<0.05), while there was no statistical difference between normal and reactive hyperplastic lymph nodes (p>0.05). Livin protein expression was exhibited to be positive in 16 of 30 cases of NHL with a positive rate of 53.3% and only 1 in reactive hyperplastic lymph nodes with a positive rate of 9.1%. In addition, Livin protein almost appeared in the cytoplasm of cells, seldom in nucleus. The expressions of both Livin mRNA and protein were positively correlated with clinical stages of NHL (p=0.023; p=0.009), B symptoms (p=0.015; p=0.026), blood beta2-microglobulin (beta2-MG, p=0.031; p=0.012) and the serum level of lactate dehydrogenase (LDH, p=0.037; p=0.007), but the expressions of Livin mRNA and protein had no significant correlation with age, sex and typing. It is concluded that the Livin mRNA and protein highly express in NHL patients and correlate with many clinical features, such as stage of NHL, B symptom, beta2-MG and LDH, therefore, the Livin may play a role in the prognosis of NHL patients. The further study on inhibitory effect of Livin expression will promote the illustration of NHL pathogenesis and contribute to the treatment and prognosis of NHL.
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PMID:[Clinical significance of Livin expression in non-Hodgkin's lymphoma]. 2041 74

Survivin is a member of the inhibitor of apoptosis family of proteins and a biomarker of poor prognosis in aggressive B cell non-Hodgkin's lymphoma. In addition to its role in inhibition of apoptosis, survivin also regulates mitosis. In this article, we show that deletion of survivin during early B cell development results in a complete block at the cycling pre-B stage. In the periphery, B cell homeostasis is not affected, but survivin-deficient B cells are unable to mount humoral responses. Correspondingly, we show that survivin is required for cell division in response to mitogenic stimulation. Thus, survivin is essential for proliferation of B cell progenitors and activated mature B cells, but is dispensable for B cell survival. Moreover, a small-molecule inhibitor of survivin strongly impaired the growth of representative B lymphoma lines in vitro, supporting the validity of survivin as an attractive therapeutic target for high-grade B cell non-Hodgkin's lymphoma.
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PMID:Essential Role for Survivin in the Proliferative Expansion of Progenitor and Mature B Cells. 2681 Feb 26


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