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)

The t(14;18) chromosomal translocation occurs in most follicular non-Hodgkin's lymphomas and places the Bcl-2 gene on chromosome 18q21 into the immunoglobulin JH region on chromosome 14q32. This translocation can be exploited to detect clonal malignant cells bearing this genetic alteration. A polymerase chain reaction (PCR) assay amplifying over the major breakpoint region (mbr) and minor cluster region (mcr) was developed and optimized. In this report, the sensitivity and reproducibility of this semiquantitative assay, performed on a relatively large number of clinical samples is shown. A titration curve of DNA made from a t(14;18)- cell line admixed with increasing ratios of a t(14;18)+ cell line was used to demonstrate that one t(14;18)+ cell in 100,000 t(14;18)- cells could reproducibly be detected. Occult lymphoma cells, not detected by standard morphologic analysis, were demonstrated in almost two-thirds of the bone marrow and peripheral blood specimens obtained from untreated patients with follicular lymphoma. Of 11 bone marrow samples assessed, seven were positive for occult disease by PCR amplification over the mbr and one was positive over the mcr. Of these six positive marrow samples, only three had been reported positive by standard morphologic criteria. In addition, seven of nine peripheral blood samples assessed were positive over the mbr and one additional sample was positive over the mcr. None of these were morphologically positive. Seven of the above patients would have been upstaged if these results were utilized for staging, including two of three patients with stage I or stage II disease. PCR-detectable occult disease persisted in four of four patients assessed both pre- and post-treatment, even after aggressive multi-drug combination chemotherapy in two of these patients. The clinical significance of detecting this occult disease must await the study of larger numbers of patients and the clinical outcomes of patients with occult disease and patients without occult disease.
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PMID:Sensitive and reproducible detection of occult disease in patients with follicular lymphoma by PCR amplification of t(14;18) both pre- and post-treatment. 841 70

The occurrence of bcl-1 and bcl-2 gene rearrangements was investigated in 37 cases of high-grade B-cell lymphomas. Bcl-2 rearrangement was detectable only in single cases of primary centroblastic lymphoma with a follicular growth pattern, whereas secondary centroblastic lymphomas evolving from a centroblastic-centrocytic lymphoma were positive in up to 60 per cent of the cases analysed. Bcl-1 rearrangement was found only in one case of immunoblastic B-cell lymphoma with a history of pre-existing lymphoplasmacytoid immunocytoma. It is concluded that there may be a subgroup of centroblastic lymphomas with a biology similar to that of centroblastic-centrocytic lymphomas. The detection of bcl-1 rearrangement in high-grade lymphomas may indicate a secondary high-grade lymphoma.
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PMID:Gene rearrangement of bcl-1 and bcl-2 is confined to distinct subgroups of high-grade malignant B-cell lymphomas. 849 22

The B-cell leukaemia/lymphoma-2 (bcl-2) proto-oncogene is unusual as its product appears to provide survival advantage to B cells by blocking apoptosis. In this study, the expression of bcl-2 has been examined in normal non-haematopoietic tissues, embryos, and psoriatic skin by immunohistochemical staining. Bcl-2 protein expression is mainly observed in cell populations with a long life and/or proliferating ability such as duct cells in exocrine glands, basal keratinocytes, cells at the bottom of colon crypts, and neurons. In the skin of both adult and embryo and also embryonic kidney and cartilage, bcl-2 expression was observed in cells which were undergoing morphological transition from undifferentiated stem cells to committed precursor cells. The finding of bcl-2 expression in the terminal differentiated syncytial trophoblast, but not cytotrophoblast, and in some cells responsive to hormone stimulation such as in the endometrium and myometrium suggests that the gene expression may be related to hormone responsiveness. As no bcl-2 localization was seen in the benign hyperproliferative skin condition psoriasis, this does not suggest a straight-forward link to proliferation. These observations support the view that the bcl-2 gene may have an important role in cell development, maturation, and the path to terminal differentiation.
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PMID:Bcl-2 expression in adult and embryonic non-haematopoietic tissues. 850 40

The most common translocation in human lymphoma, t(14;18)(q32;q21), recombines the bcl-2 gene with the immunoglobulin (Ig) heavy-chain locus leading to the production of high levels of chimeric RNAs and the resulting 26 kDa bcl-2 protein. The oncogenic role of the bcl-2 gene has been shown by the suppression of a variety of programmed cell deaths (apoptosis). Bcl-2 is able to interact with other members of the bcl-2 family through at least one of its conserved dimerization domains. Although overproduction of the wild-type protein appears sufficient for conferring a selective growth or a survival advantage to hematopoietic cells, the mode of activation of the proto-oncogene remains to be elucidated. In a first step, we examined and quantitated the expression of the bcl-2 gene in primary biopsies of non-Hodgkin's lymphomas (NHL) as well as in cell lines derived from NHLs. The results show that bcl-2 expression is found in a variety of hematopoietic lineages, but is most strongly associated with the B cell lineage. Within the B cell lineage, the expression levels vary depending on the differentiation as well as on the t(14;18) rearranged status. The quantitative measurements show high steady-state mRNA levels in early and in t(14;18) arranged B cells, whereas bcl-2 expression decreases with further B cell maturation and differentiation. In a second step we analyzed the bcl-2 mRNA for secondary genetic alterations, which may alter regulatory regions rendering it more tumorigenic. For this purpose, we chose a combined RT-PCR/SSCP method in order to screen out mutations of alleles which are not expressed. Different migration patterns of SSCP products were found only in two cell lines and subsequent sequencing revealed that the functional domains are not affected. Our data suggest that the dimerization properties of this protein are preserved in tumor cells and that modifications of the bcl-2 gene by the somatic hypermutation mechanism are not involved and do not influence the pathobiology of NHL.
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PMID:Preservation of functional and regulatory domains of expressed bcl-2 genes in non-Hodgkin's lymphoma. 855 21

Lymphomatous polyposis (LP) is generally thought to be an expression of non-Hodgkin's lymphoma (NHL) of follicular mantle cell (MC) origin. We report nine patients with LP from more than 3,500 cases of NHL studied by the Nebraska Lymphoma Study Group. Our patients differed from those reported previously in that LP represented a follicular center cell (FCC) NHL in two of the nine cases, with the remainder consisting of MC NHL. Three patients developed LP during a relapse of previously diagnosed and treated extraintestinal MC NHL (parotid gland, tonsil, and inguinal lymph node, respectively), whereas the other six patients presented with primary LP. In seven of the nine LP cases, a large mass predominated among a myriad of small polyps. The FCC cases were confined to the small intestine, whereas the MC cases were either pan-intestinal or colonic on their localization. Two MC cases studied by Southern blotting exhibited rearrangement of the bcl-1 locus. Bcl-2 rearrangement was not detected in any of the nine cases when studied by either a polymerase chain reaction-based assay (seven cases) or by Southern blotting (two cases). To date, four patients (three MC, one FCC) have experienced recurrent NHL in gastrointestinal sites. With follow-up ranging from 13 to 147 months, the entire group had a median survival of 41 months (primary MC LP:13, 13, 41, and 77 months; primary FCC LP:45 and 147 months; secondary MC LP:17, 41 and 76 months), and only one patient has died. We conclude that LP is a rare manifestation of NHL of either follicular MC or germinal center cell origin.
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PMID:Lymphomatous polyposis. A neoplasm of either follicular mantle or germinal center cell origin. 860 11

The splenic marginal zone is a morphologically and perhaps immunologically distinct B-cell compartment. Lymphomas arising from cells of the splenic marginal zone are rare. Here we describe the morphologic, immunologic, and clinical features of 14 cases. Patient age ranged from 35 to 79 years (median, 68 years) with a male-to-female ratio of 1:1.8. The spleen was uniformly enlarged (median, 1,540 g; range, 388-3,845 g) in all patients, the neoplastic infiltrate had a nodular pattern in three cases, nodular and diffuse in seven cases, and diffuse in four cases. The neoplastic cells had small to medium-sized nuclei with round, oval, or slightly indented contours, small eosinophilic nucleoli, and a moderate amount of pale cytoplasm. Extrasplenic involvement was present in 12 patients. Lymph nodes often had a vaguely nodular pattern and preservation of sinuses; bone marrow was infiltrated focally (seven cases) or diffusely (one case). Five patients had hepatic involvement. Ultrastructurally, neoplastic cells differed from other small B cells and resembled normal marginal zone cells by having long, serpentine rough endoplasmic reticulum profiles. All lymphomas marked as B cells and light chain restriction was demonstrated in 12 cases. Bcl-2 protein expression was present in all cases. Most cases (70%) were negative for DBA.44 (CD72). Plasmacytic differentiation was present in three cases. In conclusion, splenic marginal zone lymphoma is a B-cell neoplasm with distinctive clinical, morphologic, immunologic, and ultrastructural characteristics.
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PMID:Splenic marginal zone lymphoma. A distinct B-cell neoplasm. 861 26

The lytic response of lymphoid cells to glucocorticoid hormones (GC) is prototypical of the induction of apoptosis: a special form of cellular demise for the removal of unwanted or redundant cells. Initiation and execution of a death programme are therefore major checkpoints in GC-sensitivity. Although Bcl-2 protein can prevent or delay apoptosis of lymphoma and leukemia cells, exposed to multiple cytotoxic agents, its antagonism of GC-induced apoptosis appears most critical in conferring resistance to corticosteroids. Moreover, Bcl-2 may modulate GC-signalling to apoptosis through its association with fundamental cellular processes such as energy state, Ca2+ homeostasis and transmembrane transport. However, this signalling pathway can also be interrupted by Bcl-2- independent mechanisms. This review discusses the various cellular and oncogenetic factors that control GC sensitivity of leukemia/lymphoma cells and proposes a hypothesis of how GC may induce a death programme, sensitive to blockade by Bcl-2.
Leuk Lymphoma 1996 Jan
PMID:Bcl-2 expression and glucocorticoid-induced apoptosis of leukemic and lymphoma cells. 862 57

Transcriptional deregulation of the Bcl-2 gene has been demonstrated to extend cell viability via an inhibition of apoptotic cell death. Chronic lymphocytic leukemia (CLL) cells are inherently susceptible to apoptosis during short-term culture. Because increased expression of the Bcl-2 gene has been reported in CLL, we sought to correlate Bcl-2 protein expression with the in vitro propensity towards apoptosis and also clinical outcome. Immunoblot analysis of Bcl-2 protein revealed interpatient variability with nine of 42 (21%) cases demonstrating similar or greater expression than a t(14;18) containing lymphoma cell line and 18 of 42 (43%) cases demonstrating a level of expression similar to or less than that seen in normal peripheral blood lymphocytes. Bcl-2 expression did not correlate with clinical features, or with apoptosis, as measured by an in vitro DNA fragmentation assay. However, analysis of survival in the 33 untreated patients revealed significant differences based on the level of Bcl-2 expression, with higher expression being an adverse feature (P<0.02). This data suggests that Bcl-2 is important in the pathogenesis and progression of CLL and that quantitation of Bcl-2 protein may provide useful prognostic information.
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PMID:Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. 864 61

The Bcl-2 protein is capable of preventing apoptosis, and in vitro evidence suggests a role in drug resistance. It is expressed and the gene is rearranged in a proportion of cases of large-cell non-Hodgkin's lymphoma (NHL), but the clinical significance of these findings is controversial. The purpose of this study was to determine the influence of both Bcl-2 expression and major breakpoint region (MBR) bcl-2 rearrangement in a large cohort of prospectively accrued patients with intermediate-grade B-cell NHL treated in a standardized manner. All patients with Working Formulation F, G, or H NHL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in British National Lymphoma investigation studies between July 1974 and April 1992 were considered for this study if the appropriate paraffin blocks were available. Paraffin sections from the diagnostic specimen were analyzed for evidence of MBR rearrangement using a polymerase chain reaction-based method, and for Bcl-2 expression using immunohistochemistry. Failure to achieve complete remission (CR), relapse, death from NHL, and deaths from all causes were used as end points to measure CR rate, actuarial relapse rate, actuarial survival from NHL, and actuarial overall survival. One hundred sixty-one suitable patients were identified and tested for the bcl-2 MBR translocation, with 27 (17%) found to be positive; 153 of these patients were tested with immunocytochemistry, and 84 (55%) showed evidence of Bcl-2 expression. For patients who achieved CR from the initial treatment, the relapse rate was significantly higher in those with Bcl-2 expression than in those without. In addition, multivariate analysis identified Bcl-2 expression as the only factor significantly related to relapse rate in the subjects measured. The cause-specific survival for NHL in the series as a whole was significantly lower in patients with Bcl-2 expression than in those without. MBR status had no significant influence on any of the outcome measures, but the number of MBR-positive patients was relatively small, and larger studies are required. In conclusion, in Working Formulation F, G, and H NHL of B-cell type, expression of Bcl-2 protein predicted independently for relapse.
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PMID:Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin's lymphoma: a British National Lymphoma Investigation Study. 870 13

Using a Burkitt lymphoma cell line to model human B-cell apoptosis in vitro, we observed that crosslinking, by antibody, of cell surface immunoglobulin induced G1 growth-arrest followed by apoptosis. By contrast, cells treated with the Ca(2+)-ionophore, ionomycin, generated apoptotic signals in G2/M as well as in G1. Both ionomycin and anti-immunoglobulin treatment induced rapid dephosphorylation of Rb prior to apoptosis. Apoptosis was repressed following exposure to CD40-ligand and was accompanied by hyperphosphorylation of Rb and cell-cycle progression but not Bcl-2 expression. Expression of Bcl-2 protein in stable bcl-2-transfectants, also resulted in repression of apoptosis and anti-immunoglobulin-treated cells no longer underwent growth-arrest. In Bcl-2-expressing cells in which apoptosis was repressed, Rb remained hyperphosphorylated, even during G1-arrest induced by ionomycin. TGF beta treatment of Bcl-2-expressing cells induced G1-arrest, de-phosphorylation of Rb and apoptosis. These results suggest that the functional activity of Bcl-2 in B-lymphoma cells is dependent upon, or leads to, sustained hyperphosphorylation of Rb and that Rb hyperphosphorylation can be uncoupled from cell-cycle progression.
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PMID:Repression of apoptosis in human B-lymphoma cells by CD40-ligand and Bcl-2: relationship to the cell-cycle and role of the retinoblastoma protein. 871 Mar 76


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