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

At least three categories of genes are envisaged to be involved in the natural history of B-CLL. First, the genes that are responsible for the transforming event(s) in the (presently unknown) target cell; second, the gene(s) that help the progressive accumulation of malignant cells and finally the gene(s) that cause the progression toward a more aggressive lymphoma. The possibility that the clonal expansion of B-CLL is due to a prolonged life-span of monoclonal B cells rather than to an acceleration of their proliferative activity may now be reinterpreted by taking into account some recent findings on the expression of Bcl-2 gene in B-CLL cells. The Bcl-2 gene product regulates programmed cell death and a number of experiments suggest that Bcl-2 is involved in the selection and maintenance of long-lived memory B cells rescuing them from apoptotic death and leading to their accumulation in the GO phase of the cell cycle. Variant chromosomal translocations have been detected in a small fraction (5-10%) of B-CLL, involving Bcl-2 and the Ig light chain gene. Despite the low percentage of Bcl-2 rearrangements the expression of mRNA and protein is appreciable in most samples of fresh B-CLL cells in an amount comparable to that observed in Karpas 422 cells, which contain a t(14;18).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of Bcl-2 in the pathogenesis of B chronic lymphocytic leukemia. 826 Aug 92

A synergistic interaction of Bcl-2 and c-Myc plays a role in lymphomagenesis in mice and in some patients as well. Progression of follicular lymphoma to a more aggressive lymphoma is seen in the majority of patients, and approximately 10% of the transformed lymphomas have a translocation of c-myc in addition to the translocation of bcl-2 found in the original follicular lymphoma. We investigated whether transcriptional deregulation of bcl-2 and c-myc could be examined in primary lymphoma cells by in vivo footprinting and in vitro protein-DNA binding studies. A matched pair of follicular and transformed lymphoma samples was examined. The transformed lymphoma had acquired a translocation of c-myc into the immunoglobulin heavy chain locus. High levels of bcl-2 expression were observed in both the follicular and transformed lymphomas, whereas the expression of c-myc was low in the follicular lymphoma and increased in the transformed lymphoma. In vivo footprint analysis revealed that a CRE site and a Cdx site in the bcl-2 promoter were occupied on the translocated alleles but not on the normal alleles in both the follicular and transformed lymphomas. Two nuclear factor kappaB sites were occupied on the translocated c-myc allele in the transformed lymphoma. Gel shift analysis revealed that these proteins bound to their respective sites in the bcl-2 or c-myc promoter. There was no evidence that the presence of one of the translocations in the immunoglobulin heavy chain locus influenced the expression of the other translocated gene.
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PMID:Molecular mechanisms of transcriptional control of bcl-2 and c-myc in follicular and transformed lymphoma. 1143 60

The majority of follicular lymphoma and Burkitt's lymphoma are associated with reciprocal translocations involving BCL2 and cMYC, respectively. Unusual reports of aggressive lymphoma presenting with both translocations have been described as well as rare cases with a third structural alteration usually involving BCL6. The patient described here presented with aggressive high-grade lymphocytic leukemia, FAB subtype L2 (ALL-L2), and three reciprocal translocations, t(14;18)(q32;q21), t(8;14)(q24.1;q32), and t(1;2) (q22-23;p13). Despite immature morphology the leukemic blasts had a mature B-cell phenotype; they were positive for surface immunoglobulin heavy chains and negative for CD34, TdT, and CD10. Most reported dual t(14;18)/t(8;14) cases have not shown sIg and were positive for CD10. Molecular genetic analyses showed the typical rearrangements of BCL2 and cMYC as well as the FCGR2B gene on chromosome 1q23. The occurrence of a third oncogene rearrangement in association with the dual BCL2, cMYC translocations in ALL patients is very rare. To our knowledge, this is the first case where the third hit involves the FCGR2B locus. This report reiterates the poor prognosis associated with activation of cMYC together with elevated Bcl-2 expression. These data also support recent evidence that dysregulation of FCGR2B may play a role in tumor progression.
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PMID:Case of acute lymphoblastic leukemia presenting with t(14;18)/BCL2, t(8;14)/cMYC, and t(1;2)/FCGR2B. 1450 97

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with a 5-year survival rate of 35%-60%. Various clinical factors included in the International Prognostic Index have failed to identify the patients with DLBCL who will not benefit from the standard R-CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone plus rituximab) treatment regimen. Bcl-2 has been implicated in conferring resistance to chemotherapy in non-Hodgkin's lymphoma and is therefore a candidate prognostic marker in DLBCL. To identify the correlation between Bcl-2 expression and response to rituximab-containing treatment regimens, histologic materials were analyzed from 292 elderly patients with confirmed DLBCL. Of these, 155 patients had received R-CHOP (53%) and 137 had received CHOP (47%). One hundred ninety-three patients (66%) were found to express high levels of Bcl-2 protein in > 50% of the tumor cells. Of the 193 Bcl-2-positive patients, the patients who received R-CHOP had a better 5-year overall rate than patients treated with CHOP (56% vs. 42%; P = 0.01), whereas in the patients with Bcl-2-negative disease, there was no statistically significant difference in the 5-year overall survival rates between the R-CHOP and CHOP regimens (58% vs. 52%; P = 0.6). Therefore, the addition of rituximab to the standard chemotherapy regimen seems to have overcome the Bcl-2-associated resistance to chemotherapy.
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PMID:Bcl-2 gene expression as a predictor of outcome in diffuse large B-cell lymphoma. 1679 75

Constitutive activity of nuclear transcription factor kappaB (NF-kappaB) is observed in many pathological types of lymphoma that are associated with a poor clinical course. This suggests that NF-kappaB and pathways involving NF-kappaB are possible targets for successfully treating lymphoma. We examined 28 lymph nodes from 28 patients in whom follicular lymphoma was diagnosed from 1996 to 2006 at our institution, which were formalin-fixed and paraffin-embedded. The specimens were stained with an antibody that could recognize activated NF-kappaB and p65 to determine whether they were positive or negative for NF-kappaB activation. The clinical courses of the 28 patients were then correlated with the results of the NF-kappaB staining. The 10 men and 18 women had a mean age of 57.3 years (range, 25-87 years). By follicular lymphoma grade, 10 patients had grade 1, 16 had grade 2, and 2 had grade 3a. Ten patients died due to lymphoma. NF-kappaB was positive in 6 of the 28 cases. Analysis of the positive and negative staining groups while taking into account the clinical course, sex, age, grade of follicular lymphoma, prognostic index, CD10, CD23, Bcl-2, karyotype t(14;18), and survival showed that no significant differences. Six of the 28 lymph nodes (21.4%) exhibited consistent NF-kappaB activity. Three of the eleven cases that transformed to aggressive lymphoma were positive for activated NF-kappaB. Further research to clarify the significance of constitutive NF-kappaB activity in follicular lymphoma is therefore warranted.
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PMID:Constitutive activity of nuclear transcription factor kappaB is observed in follicular lymphoma. 2050 75

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that characteristically shows overexpression of cyclin-D1 due to an alteration in the t(11;14)(q13;q32) chromosomal region. Although there are some promising treatment modalities, great majority of patients with this disease remain incurable. The B-cell antigen receptor (BCR) signaling plays a crucial role in B-cell biology and lymphomagenesis. Bruton tyrosine kinase (BTK) has been identified as a key component of the BCR signaling pathway. Evidence suggests that the blockade of BTK activity by potent pharmacologic inhibitors attenuates BCR signaling and induces cell death. Notably, the expression levels and the role of BTK in MCL survival are still elusive. Here, we demonstrated a moderate to strong BTK expression in all MCL cases (n=19) compared to benign lymphoid tissues. Treatment of MCL cell lines (Mino or Jeko-1) with a potent BTK pharmacologic inhibitor, Ibrutinib, decreased phospho-BTK-Tyr(223) expression. Consistent with this observation, Ibrutinib inhibited the viability of both Mino and JeKo-1 cells in concentration- and time-dependent manners. Ibrutinib also induced a concentration-dependent apoptosis in both cell lines. Consistently, Ibrutinib treatment decreased the levels of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 protein. These findings suggest that BTK signaling plays a critical role in MCL cell survival, and the targeting of BTK could represent a promising therapeutic modality for aggressive lymphoma.
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PMID:Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by Ibrutinib induces apoptosis. 2396 69

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene product with tyrosine kinase activity and is expressed in substantial subset of anaplastic large cell lymphomas (ALCL). It has been shown that NPM-ALK binds to and activates signal transducer and activator of transcription 3 (STAT3). Although NPM-ALK(+) ALCL overall shows a better prognosis, there is a sub-group of patients who relapses and is resistant to conventional chemotherapeutic regimens. NPM-ALK is a potential target for small molecule kinase inhibitors. Crizotinib (PF-2341066) is a small, orally bioavailable molecule that inhibits growth of tumors with ALK activity as shown in a subgroup of non-small lung cancer patients with EML4-ALK expression. In this study, we have investigated the in vitro effects of Crizotinib in ALCL cell line with NPM-ALK fusion. Crizotinib induced marked downregulation of STAT3 phosphorylation, which was associated with significant apoptotic cell death. Apoptosis induction was attributed to caspase-3 cleavage and marked downregulation of the Bcl-2 family of proteins including MCL-1. These findings implicate that Crizotinib has excellent potential to treat patients with NPM-ALK(+) ALCL through induction of apoptotic cell death and downregulation of major oncogenic proteins in this aggressive lymphoma.
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PMID:Crizotinib (PF-2341066) induces apoptosis due to downregulation of pSTAT3 and BCL-2 family proteins in NPM-ALK(+) anaplastic large cell lymphoma. 2448 91

Follicular lymphoma (FL), an indolent neoplasm caused by a t(14;18) chromosomal translocation that juxtaposes the BCL2 gene and immunoglobulin locus, has a variable clinical course and frequently undergoes transformation to an aggressive lymphoma. Although BCL2 mutations have been previously described, their relationship to FL progression remains unclear. In this study, we evaluated the frequency and nature of BCL2 mutations in 2 independent cohorts of grade 1 and 2 FLs, along with the correlation between BCL2 mutations, transformation risk, and survival. The prevalence of BCL2 coding sequence mutations was 12% in FL at diagnosis and 53% at transformation (P < .0001). The presence of these BCL2 mutations at diagnosis correlated with an increased risk of transformation (hazard ratio 3.6; 95% CI, 2.0-6.2; P < .0001) and increased risk of death due to lymphoma (median survival of 9.5 years with BCL2 mutations vs 20.4 years without; P = .012). In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma. Some mutant Bcl-2 proteins exhibited enhanced antiapoptotic capacity in vitro. Accordingly, BCL2 mutations can affect antiapoptotic Bcl-2 function, are associated with increased activation-induced cytidine deaminase expression, and correlate with increased risk of transformation and death due to lymphoma.
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PMID:BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma. 2545 15