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)

Follicular lymphoma, the most common human lymphoma, characteristically has a t(14; 18) interchromosomal translocation. It is typically an indolent disease comprised of small resting B cells, but frequently develops into a high-grade lymphoma. The t(14; 18) translocates the Bcl-2 gene, generating a deregulated Bcl-2-immunoglobulin fusion gene. Bcl-2 is a novel inner mitochondrial membrane protein that extends the survival of certain cells by blocking programmed cell death. To determine the oncogenic potential of the t(14; 18) translocation, we produced transgenic mice bearing a Bcl-2-immunoglobulin minigene that structurally mimicked the t(14; 18). An indolent follicular hyperplasia in these transgenic mice progressed to a malignant diffuse large-cell lymphoma. The long latency, progression from polyclonal to monoclonal disease, and histological conversion, are all suggestive of secondary changes. Half of the immunoblastic high-grade lymphomas had a rearranged c-myc gene. Our transgenic mice provide an animal model for tumour progression in t(14; 18) lymphoma and show that prolonged B-cell life increases tumour incidence.
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PMID:Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). 198 77

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 bcl-2 gene is rearranged in most cases of follicular lymphoma and the breakpoint clusters into two specific regions: mbr and mcr. Rearrangements to immunoglobulin heavy chain genes (IgH) result in a deregulation of the gene and increased transcription of mRNA for the bcl-2 protein. In chronic lymphocytic leukaemia (CLL) expression of bcl-2 protein is increased but rearrangement of the gene can be found only in a minority of cases: commonly a variant translocation with a breakpoint region located 5' of the bcl-2 gene (vcr) with preferential rearrangement to immunoglobulin light chain genes. We have analysed breakpoints in mbr and vcr in malignant cells from 96 patients with B-CLL, 45 with hairy cell leukaemia (HCL) and 41 with high- and low-grade non-Hodgkin's lymphomas (NHL). Vcr rearrangements were observed in nine patients (12%) with B-CLL. Four patients had co-migration of rearranged bcl-2 bands to kappa genes and two patients to IgH. Cytogenetic abnormalities involving 18q21, the site of the bcl-2 gene, was found in two cases only. In several cases with bcl-2 gene rearrangement chromosomal aberrations not including 18q21 were observed. In six patients (two B-CLL, one follicular lymphoma, one immunocytoma and two high-grade lymphomas), breakpoints in both vcr and mbr were found. In HCL a rearrangement in the vcr region was found in one case. Bcl-2 protein immunostaining of B-CLL showed intense bcl-2 expression in all cases and no correlation was found between gene rearrangement and protein expression. Our study confirms that breakpoints in the bcl-2 gene commonly cluster to the vcr region in B-CLL, but in most cases over-expression of bcl-2 protein has to be explained by other mechanisms than bcl-2 gene rearrangement. We also report that simultaneous breakpoints in mbr and vcr is a recurrent phenomenon in B-CLL and in other high- and low-grade non-Hodgkin's lymphomas.
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PMID:Bcl-2 rearrangements with breakpoints in both vcr and mbr in non-Hodgkin's lymphomas and chronic lymphocytic leukaemia. 861 30

We propose that 12E7 (CD99) expression, along with TdT, bcl-2, and CD34 reactivity in lymphoblastic lymphoma (LyL)/acute lymphoblastic leukemia (ALL), distinguishes this group of neoplasms from small noncleaved cell lymphomas (SNCLs) in both pediatric and adult patients, thereby narrowing the differential diagnosis of high-grade non-Hodgkin's lymphomas and acute lymphoblastic leukemias in paraffin sections. 12E7 (CD99) is one of a group of available antibodies that recognizes the product of the mic-2 gene, which was originally identified in ALL. Despite this, most clinicopathological research has focused on the reactivity of 12E7 in a subset of the small round cell tumors of childhood. Although TdT is widely used in the subtyping of blastic leukemias, its use in the distinction of high-grade lymphomas in paraffin sections has been limited. We collected 24 cases of LyL/ALL (13 B-cell and 11 T-cell) and 15 cases of SNCL from 1984 through 1993. We confirmed the diagnoses using morphology and analysis of immunologic data. We performed immunohistochemistry with the 12E7 antibody, TdT, bcl-2, and CD34 on formalin-fixed, paraffin-embedded material. The patients' ages ranged from 4 to 81 years; nine of the study patients were children. Sixteen of the 24 LyL/ALLs stained with 12E7. In contrast, none of the 15 cases of SNCL reacted with this antibody (chi-square P < .0001). A larger percentage of T-cell LyL/ALLs reacted with 12E7 than did B-cell LyL/ALLs (82% v 54%). Sixteen of 20 LyL/ALLs reacted with the anti-TdT antibody, as compared with none of 11 SNCLs (chi-square P < .0001). Six LyL/ALLs were CD34 positive (of 23), and none of the SNCLs were CD34 positive (0 of 12) (chi-square P = .0519). Bcl-2-positive cases were found among both LyL/ ALLs and SNCLs, although they were more prevalent among LyL/ ALLs (92% v 25%; chi-square P < .0001). When one considers the differential diagnosis of a high-grade lymphoma/acute lymphoblastic leukemia, positive reactions with 12E7, TdT, bcl-2, and CD34 support the diagnosis of LyL/ALL over SNCL. Moreover, we present data that suggests that evaluating for TdT in formalin-fixed paraffin-embedded tissue is a more sensitive test than using either 12E7, bcl-2 or CD34 alone.
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PMID:MIC2, TdT, bcl-2, and CD34 expression in paraffin-embedded high-grade lymphoma/acute lymphoblastic leukemia distinguishes between distinct clinicopathologic entities. 934 23

Extranodal oral lymphomas, seen with increasing frequency in HIV infection, may have dysfunctional apoptotic mechanisms that favor tumor progression. The purpose of this study was to evaluate extranodal lymphomas from HIV-positive patients for expression of apoptosis-associated proteins. Correlations were made with 10 histologically comparable extranodal lymphomas from HIV-negative patients and 6 hyperplastic lymph nodes from otherwise healthy young adults. Formalin-fixed tissue sections were immunohistochemically stained for apoptosis-associated proteins (Bcl-2, Bcl-x, Bax, Bak, p53, MDM2, BHRF). In situ hybridization was also done on deparaffinized sections for Epstein-Barr virus EBER mRNA. Eighteen consecutive oral lymphomas were studied in HIV/AIDS-positive patients. Four of 5 intermediate-grade lymphomas expressed Bcl-2 to a greater degree than did high-grade lymphomas (4 of 13). Most lymphomas were positive for Bcl-x and Bax, and few expressed Bak. The staining patterns for these proteins were similar to those seen in HIV-negative patients. Staining patterns were relatively consistent in the hyperplastic lymph nodes, whereas such patterns were irregular in lymphomas. Positive p53 staining was seen in 11 of 18 HIV-positive cases; 9 of these were also MDM2-positive. Double stains suggested that both p53 and MDM2 proteins were expressed in the same cells in these nine cases. Epstein-Barr virus-EBER mRNA was detected in 14 of 18 cases and in 3 of 10 cases from HIV-negative patients. BHRF staining was evident in only a few cells of three HIV-positive lymphomas. The irregular expression of Bcl-2, Bcl-x, Bax, and Bak in oral lymphomas indicates dysfunctional apoptotic mechanisms in these tumors. Bcl-2 staining differs with tumor grade. Positive staining for p53 and MDM2 proteins is a notable feature of lymphomas in HIV-positive patients and may relate to binding of MDM2 to wild-type p53. Epstein-Barr virus is more commonly associated with oral lymphomas in HIV-positive patients, although the Epstein-Barr virus-produced protein BHRF, which has Bcl-2-like activity, is minimally expressed.
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PMID:Apoptosis-associated proteins in oral lymphomas from HIV-positive patients. 972 96

The BCL-2 gene was identified at the chromosomal breakpoint of t(14; 18)-bearing human follicular B cell lymphomas. BCL-2 proved to block programmed cell death rather than promote proliferation. Transgenic mice that overexpress Bcl-2 in the B cell lineage demonstrate extended cell survival and progress to high-grade lymphomas. Thus, BCL-2 initiated a new category of oncogenes, regulators of cell death. Bcl-2-deficient mice demonstrate fulminant apoptosis of lymphocytes, profound renal cell death and loss of melanocytes. BCL-2 protein duels with its counteracting twin, a partner known as BAX. When BAX is in excess, cells execute a death command; but, when BCL-2 dominates, the program is inhibited and cells survive. Bax-deficient mice display cellular hyperplasia, confirming its role as a proapoptotic molecule. An expanded family of BCL-2-related proteins shares homology clustered within four conserved regions termed BCL-2 homology 1 through 4 (BH1-4). These novel domains control the ability of these proteins to dimerize and function. An amphipathic alpha helix, BH3, is of particular importance for the proapoptotic family members. BID and BAD represent an evolving set of proapoptotic molecules, which bear sequence homology only at BH3. They appear to reside more proximal in the pathway serving as death ligands. BAD connects upstream signal transduction paths with the BCL-2 family, modulating this checkpoint for apoptosis. In the presence of survival factor interleukin-3, cells phosphorylate BAD on two serine residues. This inactivated BAD is held by the 14-3-3 protein, freeing BCL-XL and BCL-2 to promote survival. Activation of BAX results in the initiation of apoptosis. Downstream events in this program include mitochondrial dysfunction, as well as Caspase activation. The pro- and antiapoptotic BCL-2 family members represent central regulators in an evolutionarily conserved pathway of cell death. Aberrations in the BCL-2 family result in disordered homeostasis, a pathogenic event in diseases, including cancer.
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PMID:BCL-2 gene family and the regulation of programmed cell death. 1019 82

Oblimersen is an antisense oligonucleotide developed by Genta for systemic use as an injection. It comprises a phosphorothioate backbone linking 18 modified DNA bases. Oblimersen targets the first six codons of Bcl-2 mRNA to form a DNA/RNA complex. The duplex is subsequently recognised as a foreign message and is cleaved enzymatically, thereby destroying the Bcl-2 message. The Bcl-2 protein, which is a potent inhibitor of apoptosis, is overexpressed in many cancers, including follicular lymphomas, breast, colon and prostate cancers, and intermediate-/high-grade lymphomas. By reducing the amount of Bcl-2 protein in cancer cells, oblimersen may enhance the effectiveness of conventional anticancer treatments. Genta has reported results from randomised phase III trials of oblimersen in four different indications: malignant melanoma, chronic lymphocytic leukaemia (CLL), multiple myeloma and acute myleoid leukaemia (AML). A negative opinion has been issued for the company's MAA for the product in the treatment of malignant melanoma in the EU; the EMEA has indicated an additional confirmatory trial is needed in this indication for approval. An NDA for CLL was deemed non-approvable by the US FDA; the company is appealing this decision. The phase III trials in multiple myeloma and AML did not meet their primary endpoints. Phase I and II trials are also underway or have been completed for a range of other cancer types. Genta and sanofi-aventis (formerly Aventis) entered into a collaboration agreement in 2002; however, this agreement was terminated by sanofi-aventis in May 2005. Genta became solely responsible for all costs relating to oblimersen at this time. Genta expanded its Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute in November 2001. The expanded collaboration was to investigate the use of oblimersen in combination with standard anticancer therapy in a broad range of cancers. This expansion occurred following the Gensynergy project, which showed that oblimersen was synergistic with other anticancer therapies. Genta signed a 5-year manufacturing agreement with Avecia Ltd in December 2002 to supply it with oblimersen. Genta's NDA was submitted to the FDA in December 2005 and accepted for review in March 2006. The application was based on data from a phase I/II trial (NCT00021749) of oblimersen alone in approximately 40 patients and a phase III study (NCT00024440) of 241 patients who received fludarabine and cyclo-phosphamide with or without oblimersen. Genta received a Special Protocol Assessment (SPA) from the FDA in October 2006 for a randomised, pivotal, clinical trial of oblimersen in CLL. The trial will be conducted in patients who have not received prior chemotherapy and who would be randomised to receive fludarabine and rituximab with or without oblimersen. This trial has not yet begun.Fast-track status was given to oblimersen for CLL in June 2003 by the FDA. Oblimersen previously obtained orphan drug status in the US and EU for CLL in September 2001. Genta previously submitted the MAA under the centralised licensing procedure and Spain and France were assigned as rapporteur and co-rapporteur countries, respectively. It was supported by an extended 24-month follow-up of patients from a phase III study (NCT00016263) of oblimersen plus dacarbazine. The EMEA validated the MAA for review in January 2006. Genta received a number of scientific questions from the EMEA in June 2006, which the company responded to. Genta intends to file a formal complaint and a request for correction of information with the FDA under the Federal Data Quality Act. The complaint is related to a key statistical analysis of the company's data for oblimersen in the treatment of melanoma used by the FDA at the Oncology Drug Advisory Committee (ODAC) in May 2004. Genta believes that analysis sought to discredit the finding that treatment with oblimersen significantly increased progression-free survival; ODAC previously agreed this endpoint would support full approval in the absence of a survival improvement in patients with advanced melanoma.A rolling NDA submission was submitted to the FDA in the third quarter of 2003; however, Genta and Aventis withdrew the NDA after the application failed to gain marketing approval from the FDA's Oncology Drug Advisory Committee (ODAC). In May 2004, ODAC voted that phase III trial results did not provide substantial evidence of effectiveness to outweigh toxicity of oblimersen treatment in patients with metastatic melanoma. Genta has the option to resubmit this application. The FDA gave oblimersen orphan drug status for malignant melanoma in August 2000. In October 1999, fast-track status was given to oblimersen by the FDA for malignant melanoma when used in combination with dacarbazine. In addition, oblimersen received orphan drug status for malignant melanoma in Australia in October 2006.A phase III study (NCT00016263) of oblimersen in combination with dacarbazine was conducted in patients with malignant melanoma. The combination treatment did not significantly increase overall survival time, but did significantly increase progression-free survival time, compared with dacarbazine treatment alone. The phase III trial enrolled 771 patients at 140 sites in 12 different countries. Patients were randomly assigned to receive dacarbazine alone or in combination with oblimersen. The primary endpoint of this trial was to compare the overall survival between the two treatment arms. Secondary endpoints included comparative analyses of progression-free survival and tumour response. Genta will conduct another phase III study of oblimersen in patients with advanced melanoma. The trial is designed to provide additional safety and efficacy evidence of the drug, in combination with dacarbazine, in patients who have not previously received chemotherapy. Approximately 300 patients are expected to be enrolled in the trial, which is planned to begin during mid-2007, at sites throughout Europe, Australia, and North and South America. Genta is conducting a phase I clinical trial (NCT00409383) to evaluate the combination of oblimersen, ABI 007, and temozolomide in chemotherapy-naive patients with advanced melanoma. This trial was initiated in November 2006 and is the first follow-on study to Genta's phase III trial of oblimersen plus dacarbazine. Oblimersen received orphan drug status in the US and EU for multiple myeloma in September 2001. In addition, fast-track designation was given to oblimersen by the FDA in the same month.A phase I/II clinical study (NCT00062244) of oblimersen was conducted by the NCI in patients with Waldenstrom's macroglobulinaemia, a disease that is similar to multiple myeloma. The study results indicated that oblimersen may be a useful treatment in this group of patients (all had high levels of Bcl-2 expression). In June 2003, Genta and Aventis announced the presentation of clinical data from a phase II trial of oblimersen in combination with docetaxel injection concentrate for patients with advanced HRPC. Researchers reported that these findings validated progression into phase III trials. Genta has licensed eight US patents relating to oblimersen and its backbone chemistry and these expire between 2008 and 2015. Genta has two pending US patent applications that relate to oblimersen. Corresponding patent applications have been filed in Canada, Europe and Japan. Genta owns three US patents relating to methods of using oblimersen that will expire in 2020, and also has approximately 45 corresponding foreign patent applications.
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PMID:Oblimersen: Augmerosen, BCL-2 antisense oligonucleotide - Genta, G 3139, GC 3139, oblimersen sodium. 1776 97

Follicular lymphoma (FL) in situ (FLIS) was first described and proposed as a distinct entity associated with an indolent clinical course in 2002. To gain further insight into the biology of this enigmatic lymphoproliferation, we analyzed morphologic, phenotypic, cytogenetic and molecular features of tissue specimens manifesting a pattern of follicular colonization by Bcl-2(bright+)CD10(+) B-cells and associated lymphomas from 13 adults and evaluated their clinical outcomes. We observed this immunoarchitectural pattern in lymph nodes (n = 8), at extranodal sites (n = 4), or at both locations (n = 1) at diagnosis. All except 3 cases showed concomitant bright CD10 expression. Six (46%) patients had synchronous and 2 (15%) developed metachronous B-cell lymphomas, with 5 representing high-grade lymphomas. The Bcl-2(bright+)CD10(+) B-cells colonizing reactive follicles and synchronous lymphomas were clonally related in 4/5 (80%) cases analyzed and 5/6 (83%) displayed BCL2 translocations. Two cases exhibited complex karyotypes in both components; a genetic "triple hit" was detected in one instance and 2 copies of t(14,18) were observed in a lymph node biopsy lacking evidence of lymphoma from an individual with stage 4 disease, suspected on imaging, who subsequently displayed a mantle zone/perifollicular infiltrate of Bcl-2(bright+)CD10(+) B-cells in the adenoids. Our findings suggest that bright Bcl-2, and often bright CD10 expression, by B-cells colonizing reactive follicles might represent a phenomenon related to follicular homing of lymphoma, rather than being an attribute of preneoplastic FL precursors. Furthermore, due to the relatively high frequency of overt lymphomas observed, complete staging workup is recommended for patients exhibiting a Bcl-2(bright+)CD10(+) B-cell follicular colonization pattern on biopsy.
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PMID:Lymphoid follicle colonization by Bcl-2(bright+)CD10(+) B-cells ("follicular lymphoma in situ") at nodal and extranodal sites can be a manifestation of follicular homing of lymphoma. 2336 48