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)

Diffuse large B-cell lymphoma (DLBCL) can be subdivided into prognostically significant groups with germinal center B-cell-like (GCB), activated B-cell-like (ABC), and type 3 groups. In this study, tissue microarray slides composed of 163 de novo DLBCLs from Chinese patients were immunostained for CD20, CD10, Bcl-6, MUM1, CD138, Bcl-2, Ki-67, cyclin D3, geminin, and P27(Kip1). One hundred forty-nine of 163 DLBCLs could then be classified into GCB group (pattern A), activated GCB group (pattern B) and activated non-GCB group (pattern C) according to the expression of CD10, Bcl-6, MUM1, and CD138. Of the 149 cases, 40 (26%) showed pattern A expression and were grouped as GCB group, lower than reported frequency of the studies involving mostly Western population. Compared with cases with pattern A, those with pattern B (activated GCB group) and C (activated non-GCB group) more often presented with more aggressive tumors and a shorter survival time. These results indicate that most of DLBCLs from Chinese patients can be classified into prognostically different groups based on the antigenic expression models using a panel of GCB- and ABC-associated markers. Polymerase chain reaction analysis of t(14;18) showed that 11 of 64 cases were t(14;18)-positive, and most (10 of 11) of it occurred in the group with pattern A. The translocation was significantly associated with expression of Bcl-2 protein. The group with pattern B demonstrated more frequent expression of Ki-67, cyclin D3, geminin, and showed higher proliferative activity than the group with pattern A. These findings suggest that high proliferative activity of tumors with pattern B may be associated with aggressive tumor behavior and poor clinical outcome in patients with DLBCL.
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PMID:Clinicopathologic significance of immunophenotypic profiles related to germinal center and activation B-cell differentiation in diffuse large B-cell lymphoma from Chinese patients. 1844 May 93

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. The immunohistochemistry-based algorithms for the determination of the cell of origin of DLBCL have been proposed as a practical method to validate and surrogate results obtained by gene expression profiling. We studied 71 patients with primary nodal DLBCL at diagnosis, who received anthracycline-based therapy with or without rituximab. Immunohistochemistry was performed using anti-CD10, Bcl-6, MUM1 and Bcl-2 antibodies in order to assess the ontogenic profile of neoplastic cells and to verify its relation with clinical outcome. Survival data were analysed using an explorative Cox model. The immunohistochemistry-based algorithms for the determination of the cell of origin of DLBCL were not associated with prognosis. By contrast, Bcl-6 expression was associated with a longer lymphoma-free survival while immunoreactivities for MUM1 or Bcl-2 were not significantly related to patient outcome. Bcl-6 expression alone proved to be a prognostic marker in primary nodal DLBCL and seemed to be more reliable to predict clinical outcome in these disorders than the immunohistochemical algorithms for the detection of the germinal centre/non-germinal centre immunophenotype.
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PMID:Bcl-6 protein expression, and not the germinal centre immunophenotype, predicts favourable prognosis in a series of primary nodal diffuse large B-cell lymphomas: a single centre experience. 1860 21

Diffuse large B-cell lymphomas can be considered primary bone tumors if they are monostotic or polyostotic, affecting multiple skeletal sites without visceral or lymph node involvement. They are rarely considered as extranodal lymphomas or as bone tumors, respectively. To elucidate the prognostic relevance of clinicopathologic characteristics in such disease, we collected a cohort of primary diffuse large B-cell lymphomas of the bone and retrospectively investigated 33 patients. The cohort encompassed the years 1975 to 2004. Protein expression patterns were identified by immunohistochemistry applied to a tissue microarray. The patients included 23 males (mean age, 37 years) and 10 females (mean age, 54 years). Disease stage was I and II in 30 and IV in 3 patients. Within the mean follow-up of 28 months, 6 patients died. Median overall survival was reached after 78 months. Clinical factors favoring a good prognosis were age younger than 53 and administration of chemotherapy. Of the phenotypic markers analyzed (CD10, CD44s, CD138, Bcl-2, Bcl-6, MUM1, and Ki-67), MUM1 expression in more than 10% of the tumor cells and CD10 expression in less than 55% as well as a nongerminal center signature substantiated adverse outcome in a univariate model. In summary, poor survival in PB-DLBCL was clearly predicted in patients older than 53, who had not received chemotherapy, and who demonstrated MUM1 expression and nongerminal center phenotype.
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PMID:Primary diffuse large B-cell lymphomas of the bone: prognostic relevance of protein expression and clinical factors. 1861 98

Mechanisms underlying interactions between the proteasome inhibitor bortezomib and small molecule Bcl-2 antagonists were examined in GC- and ABC-type human DLBCL (diffuse lymphocytic B-cell lymphoma) cells. Concomitant or sequential exposure to non- or minimally toxic concentrations of bortezomib or other proteasome inhibitors and either HA14-1 or gossypol resulted in a striking increase in Bax/Bak conformational change/translocation, cytochrome c release, caspase activation and synergistic induction of apoptosis in both GC- and ABC-type cells. These events were associated with a sharp increase in activation of the stress kinase JNK and evidence of ER stress induction (e.g., eIF2alpha phosphorylation, activation of caspases-2 and -4, and Grp78 upregulation). Pharmacologic or genetic (e.g., shRNA knockdown) interruption of JNK signaling attenuated HA14-1/bortezomib lethality and ER stress induction. Genetic disruption of the ER stress pathway (e.g., in cells expressing caspase-4 shRNA or DN-eIF2alpha) significantly attenuated lethality. The toxicity of this regimen was independent of ROS generation. Finally, HA14-1 significantly increased bortezomib-mediated JNK activation, ER stress induction, and lethality in bortezomib-resistant cells. Collectively these findings indicate that small molecule Bcl-2 antagonists promote bortezomib-mediated mitochondrial injury and lethality in DLBCL cells in association with enhanced JNK activation and ER stress induction. They also raise the possibility that such a strategy may be effective in different DLBCL sub-types (e.g., GC- or ABC), and in bortezomib-resistant disease.
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PMID:Bcl-2 antagonists interact synergistically with bortezomib in DLBCL cells in association with JNK activation and induction of ER stress. 3111 86

Primary CNS diffuse large B-cell lymphoma (CNS DLBCL) is confined to the CNS, and constitutes a distinct entity. In the present study a series of 40 Japanese patients with CNS DLBCL who presented with neurological, but not systemic symptoms, was reviewed. Median survival was 18.7 months. CD5, CD10, Bcl-6, MUM-1, and Bcl-2 were positive in 30%, 10%, 84%, 100%, and 93% of patients, respectively. All CD10-negative patients had non-germinal center B-cell type. There was no significant difference in survival among the immunophenotypic subgroups. CNS DLBCL appeared to be homogenous as a group, which prompted the comparison with another distinct extranodal entity, intravascular large B-cell lymphoma (IVLBCL) in Japanese patients. CNS DLBCL patients did not differ in age, sex, or immunophenotype, including CD5 positivity, from IVLBCL patients, but were significantly less likely to have poor prognostic parameters than IVLBCL patients: the international prognostic index score was low or low-intermediate in 86% of CNS DLBCL patients and high or high-intermediate in 98% of IVLBCL patients. Notably, despite this difference, their survival curves almost overlapped. The present study highlights the issue of clinical distinctiveness of aggressive extranodal lymphomas, the peculiar migration and localization of which should be further clarified.
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PMID:Comparative clinicopathological study of primary CNS diffuse large B-cell lymphoma and intravascular large B-cell lymphoma. 1956 5

Diffuse large B-cell lymphoma is an aggressive type of lymphoma, potentially curable, with heterogeneous prognosis. The aim of this study was to determine prognostic significance of clinical, laboratory and immunohystochemical factors. The retrospective study was done in 50 patients with diffuse large B-cell lymphoma. The following parameters were investigated: demographic (age, sex), clinical (time to diagnosis, B symptoms, clinical stage), laboratory (erythrocyte sedimentarion rate, haemoglobin, lactate dehydrogenase, albumine), standard and revised international prognostic index, and immunohystochemical parameters, cluster designation 20, B-cell-2, and Ki67 expression. There were 20 females and 30 males, their average age being 54 (22-83) years. The majority of patients had advanced disease: B symptoms in 76%, III and IV stage in 78%, increased lactate dehydrogenase in 74%, high risk standard international prognostic index in 62% of patients. B-cell leukemia/lymphoma 2 expression was found in 57%, and high Ki67 in 62% of patients. Rituximab-Cyclophosphamnide, Hydroxydaunorubicin, Vincristine, Prednisolone and Rituximab-Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Etoposide, Prednisolone were conducted in 72% (36), and Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Prednisolone and Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Prednisolone-like treatment in 28% (14) of patients. The complete remission rate was 74%, and the partial remission rate was 9%. A significant difference in survival was found between low intermediate and high intermediate S-IPI risk groups, good and bad risk R-IPI, and patients with complete remission and patients with other treatment responses. The other parameters, including Bcl-2 and Ki67 expression, and type of treatment did not show significant influence on survival. The expected five-year survival was 69%. Our results have shown that international prognostic index, and complete remission status have prognostic significance in diffuse large B-cell lymphomas.
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PMID:[Prognostic factors in patients with diffuse large B-cell lymphoma]. 1962 49

Diffuse large B-cell lymphomas (DLBCLs) can be classified into two subtypes: germinal-centre B-cell (GCB)-like and Activated B-cell (ABC)-like tumours, which are associated with longer or shorter patient overall survival, respectively. In our previous studies, we have shown that, although DLBCL tumours of GCB-like and ABC-like subtypes express similar levels of IL4 mRNA, they exhibit distinct patterns of IL-4-induced intracellular signalling and different expression of IL-4 target genes. We hypothesized that these differences may contribute to the different clinical behaviour and outcome of DLBCL subtypes. Herein, we demonstrated that IL-4 increased the sensitivity of GCB-like DLBCL to doxorubicin-induced apoptosis and complement-dependent rituximab cell killing. In contrast, IL-4 protected ABC-like DLBCL from the cytotoxic effects of doxorubicin and rituximab. The distinct effects of IL-4 on doxorubicin sensitivity in GCB-like and ABC-like DLBCL cells may be partially attributed to the contrasting effects of the cytokine on Bcl-2 and Bad protein levels in the DLBCL subtypes. These findings suggest that the different effects of IL-4 on chemotherapy and immunotherapy-induced cytotoxicity of GCB- and ABC-like DLBCL could contribute to the different clinical outcomes exhibited by patients with these two subtypes of DLBCL.
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PMID:Interleukin-4 distinctively modifies responses of germinal centre-like and activated B-cell-like diffuse large B-cell lymphomas to immuno-chemotherapy. 1969 22

A 67-year-old man suffered from a left cervical lymph node swelling and tenderness. Biopsy of the cervical lymph node showed pleomorphic large cells containing large atypical nuclei. Immunohistochemical stains of these cells were positive for CD30, but negative for CD3 and CD20. After the biopsy, his left cervical skin was ulcerated. Biopsy of the left cervical skin was performed. Large pleomorphic cells with constricted nuclei and Reed-Sternberg-like cells existed in the dermis and epidermis. Immunohistochemical stains of the former cells were positive for CD30, CD45 and PAX5, but negative for CD3, CD10, CD20, CD15, Bcl-2, EBER ISH, EMA and ALK. He was diagnosed with diffuse large B cell lymphoma, anaplastic variant. He achieved complete remission with CHOP chemotherapy. CD30-positive DLBCL, anaplastic variant is a rare B cell lymphoma. Most of the patients presented with primary nodal disease, and skin involvement of lymphoma is very rare. This is the report of a rare case of CD30-positive DLBCL, anaplastic variant, with both nodal and skin lesions.
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PMID:CD30-positive anaplastic variant diffuse large B cell lymphoma: a rare case presented with cutaneous involvement. 2083 60

OPINION STATEMENT: The standard front-line treatment of Diffuse Large B-Cell Lymphoma (DLBCL) remains Rituximab combined with multi-agent cytotoxic chemotherapy. In spite of high response rates to this therapy, relapsed/refractory disease is observed in up to 40% of patients. It is our opinion that additional chemoimmunotherapy, followed by high-dose therapy with autologous stem cell transplant (HDT-ASCT) for responsive disease, is the optimal therapy for these patients. However, many patients cannot tolerate HDT-ASCT, or have relapsed/refractory disease in spite of it. These patients have a poor overall prognosis, and there is no clear consensus as to how these patients should be treated. Over the past decade, significant advances have been made in the understanding of the molecular genesis and subtyping of DLBCL, leading to the identification of multiple pathways and molecules that can be targeted for clinical benefit. Examples include Bcl-2, Bcl-6, cell surface markers, and myriad molecules in both the B-Cell receptor and PI3K/Akt/mTOR pathways. As agents targeting these molecules and pathways progress from preclinical models to early clinical trials, more is learned about what might predict for response to these agents, such as cell of origin classification, and/or expression of relevant molecular markers, as measured by immunohistochemistry or gene expression profiling. Both the successes and failures of these novel targeted agents promise to dramatically refine, improve, and individualize the classification and treatment of DLBCL. Therefore, it is our opinion that patients with relapsed/refractory DLBCL are an ideal population for clinical trials due to both the lack of standardized treatment, and the recent advancements in pathobiology and early-phase treatment options.
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PMID:Emerging Therapeutic Targets in Diffuse Large B-Cell Lymphoma. 2229 43

Cytokines are deregulated in cancers and can contribute to tumor growth. In patients with diffuse large-cell lymphoma (DLBCL), we observed higher levels of JAK/STAT pathway-related serum cytokines (ie, IL-6, IL-10, epidermal growth factor, and IL-2) compared with controls. Of these, only IL-10 activated the JAK2 pathway in lymphoma cells in vitro. Patients with high serum IL-10 had shorter event-free survival (EFS) than patients with low levels (P > .01) and high IL-10 was correlated with high lactase dehydrogenase (P = .0085) and higher International Prognostic Index scores (P = .01). To explore the mechanism by which IL-10 may contribute to an inferior EFS, we investigated the effect of IL-10 on the JAK2 pathway and found that the IL-10/IL-10 receptor complex up-regulated JAK2 signaling. Neutralizing Ab to IL-10 inhibited constitutive and IL-10-induced JAK2/STAT3 phosphorylation. JAK2 inhibition dephosphorylated JAK2 and STAT3 and caused an inhibitory effect on phospho-JAK2-positive DLBCL cells; there was a minimal effect on phospho-JAK2-negative cells. Apoptosis induced by JAK2 inhibition was dependent on inhibition of autocrine IL-10 and c-myc expression and independent of Bcl-2 family expression. These results provide the rationale for testing JAK2 inhibitors in DLBCL patients, and indicate that serum IL-10 may be a biomarker to identify patients more likely to respond to JAK2-targeted therapy.
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PMID:Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation. 2232 54


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