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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we analysed 34 de novo diffuse large B cell lymphoma (DLCL) from a population-based lymphoma registry for alterations of the RB1 pathway at the genetic (RB1 and CDK4) and protein (pRb, cyclin D1, cyclin D3, CDK4, and E2F-1) level. The results were correlated with the data from our previous studies of CDKN2A deletion and hypermethylation, other p53 pathway components, p27Kip1 expression, and proliferation, as well as with clinical outcome, including prognosis. We found aberrant pRb expression in four (12%) of 34 DLCLs. One of these had a point mutation in intron 3 10 bp downstream of exon 3 generating a novel splice signal. Seven tumours (21%) showed cyclin D3 overexpression, including all three thyroid lymphomas (P = 0.006). Cyclin D3 overexpression and p16INK4A/pRb aberrations were mutually exclusive, supporting an oncogenic role for cyclin D3 in DLCL. p16INK4A inactivation, cyclin D3 overexpression, or aberrant pRb expression was identified in 18 of 34 DLCLs (53%). Combining these results with our previous p53 pathway studies showed that 82% of the de novo DLCLs had alterations of these pathways, and that both pathways were altered in 13 cases (38%). Low E2F-1 expression was associated with treatment failure (P = 0.020), and multivariate analysis of overall survival identified both low E2F-1 expression (relative risk = 6.9; P = 0.0037) and p16INK4A inactivation (relative risk = 3.3; P = 0.0247) as independent prognostic markers. These data support a role of E2F-1 as tumour suppressor gene in lymphoma and strongly suggest that the RB1 and p53 pathways are important in the development of de novo DLCL. Furthermore, low E2F-1 expression and p16INK4A inactivation may serve as prognostic markers for patients with this type of lymphoma.
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PMID:Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A. 1080 23

Cyclin D3 is the most widely expressed D-type cyclin and can be rate limiting for G1/S transition. To study the expression of cyclin D3 in non-Hodgkin lymphoma, samples from 198 previously untreated patients with lymphoma from a prospectively collected, population-based lymphoma registry were analyzed immunohistochemically for cyclin D3 expression. In 43 lymphomas (21.7%), cyclin D3 was overexpressed. T-cell lymphomas more frequently overexpressed cyclin D3 than B-cell lymphomas. Furthermore, cyclin D3-overexpressing indolent lymphomas were associated with higher proliferation rate, higher p21Waf1 expression, lower p27Kip1 expression, and altered p53. Cyclin D3 overexpression identified a subgroup of patients with indolent B-cell lymphoma with adverse clinical features: patients were older, more frequently had "B" symptoms and extranodal involvement, and were more frequently in the high-intermediate or high-risk International Prognostic Index groups. At univariate analysis of indolent lymphomas, cyclin D3 overexpression was associated significantly with poor overall survival and poor relapse-free survival. The statistical significance was retained on multivariate analysis of overall survival and relapse-free survival. Our results suggest that cyclin D3 is expressed differentially among lymphoma subtypes and that overexpression might identify a subpopulation of patients with indolent lymphoma with adverse clinical features and poor outcome.
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PMID:Cyclin D3 expression in non-Hodgkin lymphoma. Correlation with other cell cycle regulators and clinical features. 1124 97

Chromosomal translocation t(6;14)(p21.1;q32.3) has been reported as a rare but recurrent event not only in myeloma and plasma cell leukemia but also in diffuse large B-cell non-Hodgkin lymphoma (B-NHL) (diffuse large B-cell lymphoma [DLBCL]) and splenic lymphoma with villous lymphocytes (SLVL); however, the nature of the target gene(s) has not been determined. This study identified t(6;14)(p21.1;q32.3) in 3 cases of transformed extranodal marginal zone B-NHL, in 1 case of SLVL, and in 1 case of a low-grade B-cell lymphoproliferative disorder. In a sixth case, a CD5(+) DLBCL, the translocation was identified by molecular cloning in the absence of cytogenetically detectable change. Two chromosomal translocation breakpoints were cloned by using long-distance inverse polymerase chain reaction methods. Comparison with the genomic sequence for chromosome 6p21.1 showed breakpoints approximately 59 and 73.5 kilobases 5' of the cyclin D3 (CCND3) gene with no other identifiable transcribed sequences in the intervening region. Although Southern blotting with derived genomic 6p21.1 probes failed to detect other rearrangements, fluorescent in situ hybridization assays, using BAC (bacterial artificial chromosome) clones spanning and flanking the CCND3 locus, along with probes for IGH confirmed localization of 6p21.1 breakpoints within the same region, as well as fusion of the CCND3 and IGH loci. Furthermore, in all cases, high-level expression of CCND3 was demonstrated at RNA and/or protein levels by Northern and Western blotting and by immunohistochemistry. These data implicate CCND3 as a dominant oncogene in the pathogenesis and transformation in several histologic subtypes of mature B-cell malignancies with t(6;14)(p21.1;q32.3) and suggest that CCND3 overexpression seen in about 10% of DLBCL cases may have a genetic basis.
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PMID:Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies. 1167 58

B-cell lymphoma, which is increasing world wide, includes such varied conditions as post-transplant lymphoproliferative disease (PTLD) and Burkitt's lymphoma. This study has characterized a role for the signalling molecule phosphatidylinositol 3-kinase, PI3K, in the regulation of growth and survival of immortalized B-lymphocytes. Burkitt's lymphoma cells die rapidly following inhibition of PI3K with LY294002, a chemical inhibitor. Furthermore, Epstein-Barr virus (EBV) immortalized B-cells, lymphoblastoid cell lines, which are a model of PTLD, do not die but are growth inhibited. This growth inhibition is due to an accumulation at G1 phase of the cell cycle and is paralleled by a loss of E2F transcriptional activity, which is essential for cell cycle entry. An active form of PI3K promotes E2F transcriptional activity in lymphoblastoid cell lines. Treatment of LCL with LY294002 causes a reduction of the expression of both cyclin D2 and cyclin D3, two key cyclins required for cell cycle progression but does not affect the expression of the EBV latent genes, EBNA2A or LMP-1. LY294002 also causes an increase in p27kip1, a cyclin dependent kinase inhibitor and results in the dephosphorylation of members of the pocket protein family. These data describe a mechanism by which PI3K plays a role in B-lymphocyte growth and suggests that a pathway from PI3K to D-type cyclin expression may provide diagnostic or treatment opportunities.
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PMID:Phosphatidylinositol 3-kinase is essential for the proliferation of lymphoblastoid cells. 1185 Aug 46

Cyclin D3 is an important regulator for transition from G(1) to the S phase of the cell cycle. Cyclin D3 expression is associated with cell proliferation in lymphoid tissues, but its impact on clinical outcome in non-Hodgkin's lymphomas has not been studied. Therefore, we determined the clinical relevance of cyclin D3 expression in patients with diffuse large B-cell lymphoma. We examined the relation between cyclin D3 expression at diagnosis and response to conventional polychemotherapy and overall survival in 81 previously untreated patients with diffuse large B-cell lymphoma. Cyclin D3 expression was assessed by immunohistochemistry. Cyclin D3 immunostaining ranged from 0-100% (median, 30%) of the lymphoma cells. Patients with high (>or=50% cyclin D3-positive lymphoma cells) cyclin D3 expression had a more advanced clinical stage (P = 0.003) and more often had extranodal disease in more than one site (P = 0.007) than patients with low cyclin D3 expression. Patients with high cyclin D3 expression had a significantly lower complete response rate (17% versus 74%; P < 0.001) and a shorter overall survival (3-year survival rate, 18% versus 74%; P < 0.001) than those with low cyclin D3 expression. Multivariate analyses that included cyclin D3 and the International Prognostic Index demonstrated that cyclin D3 expression had independent effects on the complete response rates and overall survival of the patients. In conclusion, high cyclin D3 expression is an independent predictive and prognostic factor associated with poor clinical outcome in patients with diffuse large B-cell lymphoma.
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PMID:Cyclin D3 is a predictive and prognostic factor in diffuse large B-cell lymphoma. 1189 2

Absence of a reliable method for determining the level of c-myc expression has impeded the analysis of its biological and clinical relevance in tumors. We have standardized the conditions for a real-time reverse transcription polymerase chain reaction analysis for c-myc expression, including the selection of an endogenous reference (18S rRNA), the adequate number of measurements for each sample (2 cDNA in triplicate), and suitable controls for determining inter- and intrarun variability (standard curve and calibrator). Subsequently, in a series of 56 non-Hodgkin's lymphomas, we analyzed the expression of c-myc mRNA, using real-time reverse transcription polymerase chain reaction, and of other functionally related proteins (bcl-6, p27, cyclin D3, and p53). As expected, all eight Burkitt's lymphoma cases analyzed had high levels of c-myc mRNA expression compared with that observed in reactive lymphoid tissue. There was a wider range of expression in diffuse large B-cell lymphoma, with 30% (15 of 48) of cases overexpressing c-myc. This overexpression was largely independent of c-myc translocations (4 of 5), as demonstrated by fluorescence in situ hybridization. In this large B-cell lymphoma series, a high level of c-myc expression predicted lower survival probability, irrespectively of the International Prognostic Index risk group classification. A slightly increased frequency of p53 inactivation was observed in the cases with c-myc overexpression, which suggests a growth advantage in lymphomas with concurrent deregulation of c-myc and p53. In addition, a moderate increase in bcl-6 protein expression was observed in the c-myc-positive cases, suggesting the existence of a complex interrelationship between these two genes. These findings suggest that c-myc may play a relevant role in the pathogenesis of a subset of large B-cell lymphoma and suggest the existence of additional regulatory mechanisms of c-myc expression to c-myc rearrangements.
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PMID:Development of a real-time reverse transcription polymerase chain reaction assay for c-myc expression that allows the identification of a subset of c-myc+ diffuse large B-cell lymphoma. 1259 30

We sought to determine whether identification of poor-risk subgroups of diffuse large B-cell lymphoma (DLBCL) using immunohistochemical stains would have practical utility with regard to prognosis and therapeutic decisions. Tissue microarray blocks were created using replicate samples of formalin-fixed, paraffin-embedded tissue from 200 cases of de novo DLBCL. The sections were stained with antibodies to proteins that are expressed by activated or proliferating B cells including MUM1, FOXP1, bcl-2, survivin, protein kinase C-beta (PKC-beta), cyclin D2, cyclin D3, and Ki-67. In univariate analysis, tumor expression of cyclin D2 (P = 0.025) or PKC-beta (P = 0.015) was associated with a worse overall survival, whereas none of the other markers was predictive of overall survival. Patients with DLBCL that expressed either cyclin D2 or PKC-beta had a 5-year overall survival of only 30% as compared to 52% for those who were negative for both markers (P = 0.0019). In multivariate analysis, the expression of cyclin D2 or PKC-beta was an independent predictor of poor overall survival (P = 0.035). Cyclin D2 and PKC-beta expression will be useful in designing a 'biological prognostic index' for patients with DLBCL.
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PMID:Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma. 1592 May 48

We report seven large B cell lymphoma patients showing the involvement of tumor cells with cyclin D3 (CCND3) expression in bone marrow (BM) at the initial diagnosis. All patients presented with B symptoms, splenomegaly, and anemia/thrombocytopenia lacking hemophagocytosis in the BM. Five of the seven patients had suffered from immunological diseases or cancers. The tumor cells were divided into those with a lymphoplasmacytoid or blastoid appearance. Six cases were confirmed to express CD5 antigen on tumor cells. Three cases presented a chromosomal translocation between CCND3 and the immunoglobulin heavy chain (IGH) loci, t(6;14)(p21;q32). Three and two cases showed unmutated and mutated sequences of the variable region of IGH (VH), respectively, and one case showed deletion of an entire segment of VH. Two cases with t(6;14)(p21;q32) showed an unmutated VH sequence and chromosomal translocation within the switch region of IGH. Further studies are required to determine whether CCND3 expression is associated with a unique subset of diffuse large B cell lymphoma.
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PMID:Bone marrow large B cell lymphoma bearing cyclin D3 expression: clinical, morphologic, immunophenotypic, and genotypic analyses of seven patients. 1963 71

We reviewed bone marrow studies from 351 multiple myeloma (MM) cases, selecting 12 cases (3.4%) with predominantly small lymphocyte-like morphologic features resembling B-cell lymphoma, and correlated their genetic and clinical features. All exhibited a diffuse interstitial pattern of marrow involvement. Small lymphocyte-like plasma cells were all CD45- with bright CD38 and CD138 expression and CD20 expression in 5 cases. No case had an increase in bone marrow B lymphocytes by flow cytometry. Of 12 cases, 9 were classified as the CD-2 molecular class by gene expression profiling (GEP). The 29 CD-2 class cases with (n = 9) and without (n = 20) small lymphocyte-like features could not be discerned from one another using global GEP. Event-free, but not overall, survival was significantly better in cases with small lymphocyte-like features among those sharing the CD-2 subtype. Small lymphocyte-like MM is a rare, morphologically challenging variant distinguished from B-cell lymphoma by lack of CD45 and presence of CD138 and the clinical presentation of MM. Most cases share a common GEP signature dominated by hyperexpression of cyclin D1 or cyclin D3 genes, with increased expression of the B-cell genes CD20 and VPREB3.
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PMID:Clinical, immunophenotypic, and genetic characterization of small lymphocyte-like plasma cell myeloma: a potential mimic of mature B-cell lymphoma. 2009 36

Genomic changes disrupting the expression of cyclin D3 are associated with aberrant growth of several human B-lymphoid malignancies. We demonstrate that the human diffuse large B-cell lymphoma (DLBCL), OCI-LY18 (LY18) expresses cyclin D3 but not cyclins D1 and D2. RNA interference was used to deplete cyclin D3 from LY18 cells. Surprisingly, knockdown of cyclin D3 did not inhibit pRb phosphorylation on cdk4/6- and cdk2-specific residues or measurably affect viability and proliferation. These results suggest that cyclin D3 is dispensable in LY18 cell proliferation and survival. Similar results were obtained following depletion of cyclin E. By contrast, combined knockdown of cyclins D3 and E had substantial consequences leading to G(1)-phase arrest and inhibition of proliferation. Whereas cell cycle distribution was not affected following individual depletion of cdk4, cdk6 or cdk2, the combined knockdown of cdk4 and cdk6 led to accumulation of LY18 cells in G(1)-phase of the cell cycle and inhibition of proliferation. Likewise treatment of LY18 cells with 2-Bromo-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione, a selective inhibitor of cdk4/6, led to inhibition of proliferation. Taken together, these results uncover a built-in redundancy with cyclins D3 and E for G(1)-S progression. Moreover these findings highlight the rationale for simultaneous disruption of cdk4/6 as a potential therapeutic cancer strategy.
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PMID:Cyclin D3 is dispensable for human diffuse large B-cell lymphoma survival and growth: evidence for redundancy with cyclin E. 2070 96


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