Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report an instructive case of diffuse large B-cell lymphoma presenting as acute heart failure. A 69-year-old human immunodeficiency virus-negative man was admitted to our hospital for general fatigue. A computed tomographic scan of the chest and abdomen showed pericardial effusion, but there was no evidence of tumor masses, lymph node enlargement, or hepatosplenomegaly. During the chemotherapy, increased lactate dehydrogenase and pleural effusion appeared. The tumor cells in the effusion showed positivity for CD5, CD19, CD20, kappa chain, and Bcl-2 and negativity for CD10 and CD23. The chromosomes showed t(8;14)(q24;q32) with c-myc/immunoglobulin (Ig)H rearrangement, and the MIB-1 index was not high (60%). Neither human herpes virus 8 nor Epstein-Barr virus DNA was detected in the cells by polymerase chain reaction. The response to chemotherapy was very poor, and the patient died 4 months after the diagnosis. A spectrum of the symptoms of CD5+ lymphoma encompasses pericardial effusion and also can accompany c-myc/IgH rearrangement.
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PMID:CD5+ diffuse large B-cell lymphoma with c-myc/IgH rearrangement presenting as primary effusion lymphoma. 1591 62

The expression of P53, Bcl-2, Bax, Bag-1, and Mcl-1 proteins in CD5/CD20-positive B-chronic lymphocytic leukemia (B-CLL) cells from 30 typical CLL patients was evaluated before and after 48 h of incubation with 10(-6) M fludarabine using multiparametric flow cytometric analysis. Protein expression was correlated with annexin V expression, Rai modified clinical staging, lymphocyte doubling time, and previous treatment. Our main goal was to determine the predictive value of these proteins in CLL cells in terms of disease evolution. Bcl-2 expression decreased from a median fluorescence index (MFI) of 331.71 +/- 42.2 to 245.81 +/- 52.2 (P < 0.001) after fludarabine treatment, but there was no difference between viable cells (331.57 +/- 44.6 MFI) and apoptotic cells (331.71 +/- 42.2 MFI) before incubation (P = 0.859). Bax expression was higher in viable cells (156.24 +/- 32.2 MFI) than in apoptotic cells (133.56 +/- 35.7 MFI) before incubation, probably reflecting defective apoptosis in CLL (P = 0.001). Mcl-1 expression was increased in fludarabine-resistant cells and seemed to be a remarkable protein for the inhibition of the apoptotic process in CLL (from 233.59 +/- 29.8 to 252.04 +/- 35.5; P = 0.033). After fludarabine treatment, Bag-1 expression was increased in fludarabine-resistant cells (from 425.55 +/- 39.3 to 447.49 +/- 34.5 MFI, P = 0.012), and interestingly, this higher expression occurred in patients who had a short lymphocyte doubling time (P = 0.022). Therefore, we could assume that Bag-1 expression in such situation might identify CLL patients who will need treatment earlier.
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PMID:Fludarabine induces apoptosis in chronic lymphocytic leukemia--the role of P53, Bcl-2, Bax, Mcl-1, and Bag-1 proteins. 1650 12

Drug development in human chronic lymphocytic leukemia (CLL) has been limited by lack of a suitable animal model to adequately assess pharmacologic properties relevant to clinical application. A recently described TCL-1 transgenic mouse develops a chronic B-cell CD5(+) leukemia that might be useful for such studies. Following confirmation of the natural history of this leukemia in the transgenic mice, we demonstrated that the transformed murine lymphocytes express relevant therapeutic targets (Bcl-2, Mcl-1, AKT, PDK1, and DNMT1), wild-type p53 status, and in vitro sensitivity to therapeutic agents relevant to the treatment of human CLL. We then demonstrated the in vivo clinical activity of low-dose fludarabine in transgenic TCL-1 mice with active leukemia. These studies demonstrated both early reduction in blood-lymphocyte count and spleen size and prolongation of survival (P = .046) compared with control mice. Similar to human CLL, an emergence of resistance was noted with fludarabine treatment in vivo. Overall, these studies suggest that the TCL-1 transgenic leukemia mouse model has similar clinical and therapeutic response properties to human CLL and may therefore serve as a useful in vivo tool to screen new drugs for subsequent development in CLL.
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PMID:Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia. 1667 Feb 63

TCR signaling plays a governing role in both the survival and differentiation of bipotent double-positive thymocytes into the CD4(+) and CD8(+) single-positive T cell lineages. A central mediator of this developmental program is the small GTPase Ras, emitting cytoplasmic signals through downstream MAPK pathways and eventually affecting gene expression. TCR signal transduction orchestrates the activation of Ras by integrating at least two Ras-guanyl nucleotide exchange factors, RasGRP1 and Sos. In this study, we have characterized the relationship between RasGRP1 function and its potential roles in promoting ERK activity, cell survival, maturation, and lineage commitment. Investigations on RasGRP1(-/-) mice expressing a transgenic (Tg) MHC class II-restricted TCR revealed that the development of CD4 T cells expressing this Tg TCR is completely dependent on RasGRP1. Unexpectedly, a small number of functional CD8 single-positive thymocytes expressing the Tg MHC class II-restricted TCR exists in mutant mice. In addition, RasGRP1(-/-) double-positive thymocytes exhibit marked deficits in TCR-stimulated up-regulation of the positive selection marker CD69 and the antiapoptotic protein Bcl-2, whereas CD5 induction is unaffected. To evaluate the role of RasGRP1 in providing cellular survival signaling, we enforced Bcl-2 expression in RasGRP1(-/-) thymocytes. These studies demonstrate that RasGRP1 function cannot be fully complemented by Tg Bcl-2 expression. Therefore, we propose that RasGRP1 transmits differentiation signaling critically required for CD4 T cell development.
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PMID:RasGRP1 transmits prodifferentiation TCR signaling that is crucial for CD4 T cell development. 1684 53

In this study, we compared the rate of spontaneous apoptosis of B cells from umbilical cord blood with adult B cells and assessed the role of Bcl-2, CD5, interleukin (IL)-4 and B cell-activating factor in B cell spontaneous apoptosis. We found that spontaneous apoptosis of cultured B cells, as assessed by utilizing annexin-V binding, was significantly higher in cord blood than in healthy adult individuals (77.5; 95 CI, 73.5-81.5 versus 59.2; 95 CI, 54-64, respectively, P < 0.0001) and further confirmed by 4' 6-diamidino-2-phenylindole, dihydrochloride (DAPI) staining. Whereas the expression of B cell-activating factor from the tumour necrosis factor family (BAFF) receptor mRNA was similar in B cells from adults and cord blood, we detected lower levels of circulating BAFF in the serum of cord blood (0.68 +/- 0.13 ng versus 1.83 +/- 0.54 ng, P = 0.01). The latter may explain, in part, our observation of lower levels of mean fluorescence intensity of Bcl-2 in cord B cells compared with adults (1.6 +/- 0.9 versus 2.85 +/- 1.3, P = 0.033). CD19(+) CD5(+) B cells from cord blood underwent a lower rate of apoptosis in comparison to CD19(+) CD5(-) B cells (25.1 +/- 9.3%versus 58.5 +/- 12.5%, P < 0.0001). This pattern of sensitivity was comparable in adult blood (15 +/- 5.5%versus 22.7 +/- 9.3%, P = 0.01). Nevertheless, the rate of apoptosis was higher in CD19(+) CD5(+) from cord blood compared to CD19(+) CD5(+) from adults (25.1 +/- 9.3%versus 15 +/- 5.5%, P = 0.0013). The addition of rIL-4 (10 u/ml) to cultured cells decreased B cell apoptosis in a similar fashion in both cord and adults blood. This rescue was strengthened when BAFF (100 microg/ml) was further added. Thus, alterations in Bcl-2 or serum BAFF level may explain the increased rate of cord blood B cell apoptosis.
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PMID:Increased susceptibility of cord blood B lymphocytes to undergo spontaneous apoptosis. 1690 27

Protein kinase B (PKB), an Ag receptor activated serine-threonine kinase, controls various cellular processes including proliferation and survival. However, PKB function in thymocyte development is still unclear. We report PKB as an important negative regulator of the calcineurin (CN)-regulated transcription factor NFAT in early T cell differentiation. Expression of a hyperactive version of CN induces a profound block at the CD25+CD44- double-negative (DN) 3 stage of T cell development. We correlate this arrest with up-regulation of Bcl-2, CD2, CD5, and CD27 proteins and constitutive activation of NFAT but a severe impairment of Rag1, Rag2, and intracellular TCR-beta as well as intracellular TCR-gammadelta protein expression. Intriguingly, simultaneous expression of active myristoylated PKB inhibits nuclear NFAT activity, restores Rag activity, and enables DN3 cells to undergo normal differentiation and expansion. A correlation between the loss of NFAT activity and Rag1 and Rag2 expression is also found in myristoylated PKB-induced CD4+ lymphoma cells. Furthermore, ectopic expression of NFAT inhibits Rag2 promoter activity in EL4 cells, and in vivo binding of NFATc1 to the Rag1 and Rag2 promoter and cis-acting transcription regulatory elements is verified by chromatin immunoprecipitation analysis. The regulation of CN/NFAT signaling by PKB may thus control receptor regulated changes in Rag expression and constitute a signaling pathway important for differentiation processes in the thymus and periphery.
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PMID:PKB rescues calcineurin/NFAT-induced arrest of Rag expression and pre-T cell differentiation. 1698 94

Intravascular large B-cell lymphoma (IVLBCL) is pathologically distinct with a broad clinical spectrum and immunophenotypic heterogeneity. A series of 96 patients with IVLBCL (median age, 67 years; range, 41-85 years; 50 men) was reviewed. Anemia/thrombocytopenia (84%), hepatosplenomegaly (77%), B symptoms (76%), bone marrow involvement (75%), and hemophagocytosis (61%) were frequently observed. The International Prognostic Index score was high or high-intermediate in 92%. For 62 patients receiving anthracycline-based chemotherapies, median survival was 13 months. CD5, CD10, Bcl-6, MUM1, and Bcl-2 were positive in 38%, 13%, 26%, 95%, and 91% of tumors, respectively. All 59 CD10- IVLBCL cases examined were nongerminal center B-cell type because they lacked the Bcl-6+MUM1- immunophenotype. CD5 positivity was associated with a higher prevalence of marrow/blood involvement and thrombocytopenia and a lower frequency of neurologic abnormalities among patients with CD10-IVLBCL. Compared with 97 cases of de novo CD5+CD10-diffuse LBCL, 31 cases of CD5+CD10-IVLBCL exhibited higher frequencies of poor prognostic parameters, except age. Multivariate analysis in IVLBCL revealed that a lack of anthracycline-based chemotherapies (P<.001, hazard ratio [HR]: 9.256), age older than 60 years (P=.012, HR: 2.459), and thrombocytopenia less than 100x10(9)/L (P=.012, HR: 2.427) were independently unfavorable prognostic factors; CD5 positivity was not. Beyond immunophenotypic diversity, IVLBCL constitutes a unique group with aggressive behavior.
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PMID:Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. 1698 83

Nasal NK/T-cell lymphoma is a rare disease entity with a poor outcome. Expression of antiapoptotic proteins has not been extensively investigated in this entity. Forty-eight patients with nasal T/NK-cell lymphoma who received first-line polychemotherapy (n = 44) or chemoradiotherapy (n = 4) were analyzed for expression of active caspase-3 (aC3), granzyme B protease inhibitor 9 (PI9), and Bcl-2 proteins. Lymphomas were CD3+/CD5-/granzyme B+ and EBV-associated. Median age was 46 years. Stage I/II disease was present in 75% of the cases and an International Prognostic Index (IPI) score less than 1 in 65%. With a median follow-up of 6.3 years, 5-year event-free survival (EFS) and overall survival (OS) rates were 39% and 49%, respectively. Apoptotic index was scored as high in 32% of cases and PI9 expression as positive in 68%, whereas 35% disclosed a high number of aC3+ tumor cells. Univariate analysis showed that absence of PI9 and low apoptotic index were associated with poor outcome, but not aC3 expression nor IPI score. By multivariate analysis, both parameters affected independently EFS (P = .02 and .08, respectively) and OS (P = .009 and .04). In view of its constitutive expression by normal NK cells, it is suggested that loss of PI9 expression in tumor cells may reflect some mechanism associated with progression.
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PMID:Expression of the granzyme B inhibitor PI9 predicts outcome in nasal NK/T-cell lymphoma: results of a Western series of 48 patients treated with first-line polychemotherapy within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials. 1707 22

The aim of study was to investigate the lymphocyte changes in peripheral blood of patients with Graves's disease accompanied by hematocytopenia and to explore its pathogenesis. The quantity and ratio of Th(2), Th(1), CD5(+) B, Bcl-2 level in 24 Graves's disease patients with hematocytopenia were detected by FACS, and 18 adults were selected as normal controls. The results indicated that the percentages of Th(1), Th(2), ratio of Th(2)/Th(1), CD5(+) B, Bcl-2 level in peripheral blood of the patients were (0.81 +/- 0.45)%, (6.83 +/- 3.02)%, (20.55 +/- 6.15)%, (20.89 +/- 1.62)%, (80.25 +/- 15.56)%, respectively, and were higher than those of normal controls [(0.39 +/- 0.24)% (P<0.05), (0.28 +/- 0.15)% (P<0.01), (0.52 +/- 0.12)% (P<0.01), (7.89 +/- 0.38)% (P<0.05), (36.49 +/- 6.79)% (P<0.05)]. It is concluded that the pathogenesis of Graves's disease with hematocytopenia may be related to unbalance of Th(1)/Th(2), increase of Th(2) inducing over-expression of CD5(+) B and Bcl-2 on B cell.
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PMID:[Lymphocyte changes in patients with Graves's disease accompanied by hematocytopenia]. 1749 63

Marginal zone B-cell lymphoma of the pulmonary mucosa-associated lymphoid tissue type (pulmonary MALT-MZL), a common kind of primary pulmonary lymphoma, is rare in pulmonary malignant tumors. One patient in our hospital was diagnosed by bronchoscope and the literatures on the subject were reviewed. The patient presented with periodical fever, cough and chest pain, and antibiotic therapy had no use. Chest CT scan showed the consolidation of right middle lobe and left lower lobe with CT angiogram signs, air bronchograms and distended bronchi. Pleural effusion in the left thorax mainly consisted of monocytes. Monoclonal protein was found in the electrophoresis of serum protein. Bronchial stenosis and swollen mucosa were seen with bronchoscope. The tissue section of transbronchial lung biopsy (TBLB) specimens showed diffusedly infiltrated small lymphocytes and a lymphoepithelial lesion. CD20 was positive and CD3, CD5, CD10, CD21, CD23, bcl2, bcl6 were negative in immunohistochemical stain. The clinical manifestations of pulmonary MALT-MZL are nonspecific and misdiagnosis is common, Appropriate invasive biopsy procedures are necessary for early diagnosis. Presentations such as periodical fever, distended bronchi in pulmonary consolidation, monoclonal protein might indicate diagnosis. Treatment includes surgical resection, radiotherapy and chemotherapy. Pulmonary MALT-MZL belongs to inert lymphoma and prognosis is relatively good.
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PMID:[A case of marginal zone B-cell lymphoma of the pulmonary mucosa-associated lymphoid tissue type]. 1765 56


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