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

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

Chromosomal rearrangements in non-Hodgkin's B-cell lymphoma implicate BCL-6 as an oncogene, yet direct evidence for BCL-6 acting as an oncogene in B cells has been lacking. Here, we show that BCL-6 can immortalize primary B cells, but only in the absence of p53 tumor suppressor function. The expression of BCL-6 led to greatly increased B-cell proliferation, particularly in response to CD40 stimulation. Furthermore, BCL-6-infected p53-deficient B cells gave rise to immortalized cell lines that could be maintained by CD40 stimulation. We found that in primary mouse B cells, BCL-6 repressed expression of the Blimp-1, p27kip1, and cyclin D2 target genes. BCL-6 did not markedly repress the PDCD2 and BCL-XL target genes. The BCL-6 immortalized cell lines had a phenotype consistent with germinal center B cells, they expressed the germinal center-specific M17 gene, and a significant fraction of the cells stained positive with PNA. Our data indicate that BCL-6 may act to maintain B cells in a germinal center-like state, and repression of Blimp-1 by BCL-6 may be particularly crucial for stabilization of the germinal center phenotype. Our data also suggest that disruption of the p53 pathway may be crucial for the development of BCL-6-expressing B-cell lymphomas.
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PMID:Transcriptional repressor BCL-6 immortalizes germinal center-like B cells in the absence of p53 function. 1473 19

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

Mantle cell lymphoma (MCL) is a rare B-cell lymphoma that has never been characterized in Taiwan. The purpose of the present paper was to retrospectively identify 21 cases in male patients, with a median age of 61, involving lymph node (91%), marrow (71%), and peripheral blood (23%). Eighteen (86%) were in stages III/IV with 1 and 5 year survival rates of 78% and 17%, respectively. Mixed nodular and diffuse pattern (45%) was most common while interstitial pattern (92%) predominated in marrow. Eighteen (86%) were of classical morphology, two were pleomorphic and one was blastic. The tumors expressed IgM and bcl-2 (100%), cyclin D1 (95%), CD5 (86%), CD43 and IgD (62%), CD52 (60%), and bcl-6 (5%). Ki-67 index>or=30% (P=0.1834) was associated with a trend toward poorer survival while p21, p27, or p53 expression was not statistically significant for survival. Real-time polymerase chain reaction for cyclin D1 (CCND1) gene mRNA expression showed high levels in nine cyclin D1-positive patients and a low level in the single cyclin D1-negative patient. The latter patient was cyclin D2 positive and negative for immunoglubuin heavy chain gene and CCND1 gene translocation by locus-specific interphase fluorescent in situ hybridization. In conclusion, it is confirmed that the usual morphological variants and aberrant immunophenotype of MCL in the West occur in Taiwan and that this disease carries a poor prognosis.
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PMID:Mantle cell lymphoma in Taiwan: clinicopathological and molecular study of 21 cases including one cyclin D1-negative tumor expressing cyclin D2. 1687 38

Cyclin-dependent protein kinase 6 (CDK6), in cooperation with cyclin Ds, drives cell cycle progression from G1 to S phase through phosphorylation and subsequent inactivation of retinoblastoma 1 protein. Alteration of this pathway results in both nonhematologic and hematologic malignancies, which include a small subset of B-cell lymphoproliferative disorders (BLPDs). We identified 5 cases of BLPD that carried CDK6 chromosomal translocations and characterized their clinical, pathologic, immunophenotypic, and genetic features. Common clinical characteristics included marked neoplastic lymphocytosis, systemic lymphadenopathy, splenomegaly, and bone marrow involvement. Three patients were diagnosed with low-grade B-cell lymphoma and had an indolent clinical course, and 2 patients (one who transformed to large B-cell lymphoma, and the other who was initially diagnosed with a high-grade B-cell lymphoma) had an aggressive clinical course. Immunophenotypically, the neoplastic B cells expressed CD5, CDK6, and cytoplasmic retinoblastoma 1 protein in all cases, expressed phospho-RB, p27kip1, and cyclin D2 in most cases, and uniformly lacked expression of all other cyclins. In 4 cases, the CDK6 translocation partner was kappa immunoglobulin light-chain gene; and in the fifth case, the CDK6 translocation partner was unknown. These distinct clinicopathologic and cytogenetic features distinguish the CDK6 translocation-associated BLPDs (CDK6-BLPDs) from other mature B-cell lymphomas.
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PMID:Clinicopathologic features of CDK6 translocation-associated B-cell lymphoproliferative disorders. 1914 99

SOX11 is mainly correlated with embryo neurogenesis and remodeling of tissues. D cyclins (cyclin D1, cyclin D2, and cyclin D3) work in cell transformation. We assessed the expression of SOX11, cyclin D1, cyclin D2, and cyclin D3 mRNA in 152 patients with B-cell lymphocytic proliferative diseases (B-LPD) using qRT-PCR and we detected SOX11 protein using immunohistochemistry in 15 B-LPD patients, to clarify the clinical significance of the four genes in B-LPD. Data showed the transcriptional levels of SOX11 and cyclin D1 were higher for the mantle cell lymphoma (MCL) samples compared with chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), hairy cell leukemia (HCL), splenic marginal zone lymphoma (SMZL), and healthy collators. The expression levels of cyclin D1 and cyclin D2 were both higher in DLBCL than in SMZL. The expression levels of the four genes were highly related to each other. Three of 4 MCL patients showed nuclear staining for SOX11, while other 11 B-LPD examples were negative. Furthermore, we also found the ZAP70-positive CLL patients had higher SOX11 expression levels than ZAP70-negative CLL patients. It was revealed that MCL patients have higher expression levels of SOX11 and cyclin D1 mRNA, specially expressed nuclear SOX11 protein.
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PMID:The expression of SOX11, cyclin D1, cyclin D2, and cyclin D3 in B-cell lymphocytic proliferative diseases. 2147 97

Gene expression depends on binding of transcriptional regulators to gene promoters, a process controlled by signalling pathways. The transcriptional repressor B-cell lymphoma (BCL)-6 downregulates genes involved in cell-cycle progression and becomes inactivated following phosphorylation by the Rac1 GTPase-activated protein kinase PAK1. Interestingly, the DNA motifs recognized by BCL-6 and signal transducers and activators of transcription 5 (STAT5) are similar. Because STAT5 stimulation in epithelial cells can also be triggered by Rac1 signalling, we asked whether both factors have opposing roles in transcriptional regulation and whether Rac1 signalling may coordinate a transcription factor switch. We used chromatin immunoprecipitation to show that active Rac1 promotes release of the repressor BCL-6 while increasing binding of STAT5A to a BCL-6-regulated reporter gene. We further show in colorectal cell lines that the endogenous activation status of the Rac1/PAK1 pathway correlated with the phosphorylation status of BCL-6 and STAT5A. Three cellular genes (cyclin D2, p15(INK4B), small ubiquitin-like modifier 1) were identified to be inversely regulated by BCL-6 and STAT5A and responded to Rac1 signalling with increased expression and corresponding changes in promoter occupancy. Together, our data show that Rac1 signalling controls a group of target genes that are repressed by BCL-6 and activated by STAT5A, providing novel insights into the modulation of gene transcription by GTPase signalling.
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PMID:Rac1 signalling modulates a STAT5/BCL-6 transcriptional switch on cell-cycle-associated target gene promoters. 2272 77

D-type cyclins are involved in cell cycle regulation and play an important role in the pathogenesis of lymphomas. Aberrant expression of cyclin D1 is associated with mantle cell lymphoma (MCL) and serves as a diagnostic marker of MCL. Analysis of cyclin D expression in tumor tissues of patients with diffuse large B-cell lymphoma (DLBCL) which comprises a heterogeneous group of tumors may contribute to their stratification. We analyzed expression of cyclin D1, D2, and D3 mRNAs in 30 MCL and 104 DLBCL patients using qRT-PCR and addressed their significance for disease outcome. We confirmed a high level of cyclin D1 mRNA in 29 MCL cases (97%). One case (3%) was identified as positive for cyclin D2. Expression of cyclin D1 was limited to MCL and did not occur in DLBCL. Overexpression of cyclin D2, which is rare in MCL, occurred more frequently in DLBCL (11 cases, 10.6%). We showed that high expression of cyclin D2 in DLBCL cases de novo decreased the overall survival rate (P=0.016) and progression-free survival (P=0.009). The expression pattern of cyclin D3 was similar in both types of studied lymphomas and it did not affect the disease outcome.
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PMID:Expression of D-type cyclins in mantle cell and diffuse large B-cell lymphomas. 2698 65

Activating transcription factor 6 (ATF6), a sensor protein located in the endoplasmic reticulum (ER) membrane, is an important factor in the ER stress signaling pathway. ER stress is known to be involved in folliculogenesis, follicular growth, and ovulation; however, the physiological function of ATF6 in mouse granulosa cells remains largely unknown. The aim of this study was to assess the role of ATF6 in mouse granulosa cells with respect to apoptosis, the cell cycle, and steroid hormone production, as well as several key genes related to follicular development, via RNA interference, immunohistochemical staining, real-time quantitative PCR, Western blotting, flow cytometry, terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling (TUNEL) assay, and ELISA. Immunohistochemical staining revealed that ATF6 was extensively distributed in the granulosa cells of various ovarian follicles and oocytes in adult female mice. FSH or LH treatment significantly increased ATF6 protein levels in mouse granulosa cells. In the meantime, a recombinant plasmid was used to deplete ATF6 successfully using short hairpin RNA-mediated interference technology, which was verified at both the mRNA and protein levels. Flow cytometry and TUNEL assay analysis indicated that ATF6 depletion decreased apoptosis and arrested the S phase of the cell cycle in mouse granulosa cells. Consistent with these results, p53, caspase-3, B cell lymphoma 2 (Bcl-2)-associated X protein, CCAAT-enhancer-binding protein homologous protein, cyclin A1, cyclin B1, and cyclin D2 mRNA expression decreased, whereas Bcl-2 and glucose-regulated protein 78 kDa mRNA expression increased. Interestingly, ATF6 knockdown obviously increased progesterone and estradiol production in mouse granulosa cells. Cytochrome P450 1b1 (Cyp1b1) mRNA levels were downregulated, whereas Cyp11a1, steroidogenic acute regulatory, and Cyp19a1 mRNA levels were upregulated, in keeping with the changes in steroid hormones. Furthermore, ATF6 disruption remarkably increased insulin-like growth factor binding protein4 (Igfbp4) expression and decreased hyaluronan synthase 2 (Has2), prostaglandin-endoperoxide synthase 2 (Ptgs2), and prostaglandin F receptor (Ptgfr) expression in mouse granulosa cells, which are proteins crucial for follicular development. But, after treating with tunicamycin, the levels of Has2, Ptgs2, and Ptgfr increased relatively, whereas Igfbp4 expression decreased. Collectively, these results imply that ATF6, as a key player in ER stress signaling, may regulate apoptosis, the cell cycle, steroid hormone synthesis, and other modulators related to folliculogenesis in mouse granulosa cells, which may indirectly be involved in the development, ovulation, and atresia of ovarian follicles by affecting the physiological function of granulosa cells. The present study extends our understanding and provides new insights into the physiological significance of ATF6, a key signal transducer of ER stress, in ovarian granulosa cells.
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PMID:ATF6 knockdown decreases apoptosis, arrests the S phase of the cell cycle, and increases steroid hormone production in mouse granulosa cells. 2810 Apr 84

The present study aimed to investigate microRNA-376a (miR-376a) expression in lymphoma, and to investigate the effect of miR-376a on cell proliferation and apoptosis at cytological and molecular levels. The expression of miR-376a in lymphoma issue and cells was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR), the expression of forkhead box protein P2 (FOXP2) was detected by RT-qPCR and western blot analysis, and the effect of miR-376a on cell proliferation and apoptosis were studied by an MTT assay and flow cytometry, respectively. Additionally, the expression levels of cyclin D2, cyclin A, cyclin B, apoptosis-associated proteins B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected by western blot analysis. Furthermore, the target of miR-376a was predicted and clarified using a dual-luciferase reporter assay. The expression of miR-376a was downregulated and FOXP2 was upregulated in lymphoma tissues and cells. miR-376a overexpression inhibited lymphoma cell proliferation and induced apoptosis by regulating the expression levels of cyclin D2, cyclin A, Bax and Bcl-2. The dual-luciferase reporter assay demonstrated that FOXP2 was a target of miR-376a. miR-376a overexpression induced apoptosis by targeting FOXP2. Overexpression of miR-376a inhibited cell proliferation and induced apoptosis by targeting FOXP2 in lymphoma. Therefore, miR-376a and FOXP2 have the potential for use as biomarkers of lymphoma.
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PMID:MicroRNA-376a regulates cell proliferation and apoptosis by targeting forkhead box protein P2 in lymphoma. 3012 11


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