UMLS:C0079731 - FACTA Search

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

Primary mediastinal B-cell lymphoma (PMBL) is a highly aggressive tumour with a unique pattern of clinical, morphological, immunological and genetic features distinct from other diffuse large B-cell lymphomas. PMBLs are characterized by a mature B-cell phenotype, but they typically lack immunoglobulin (Ig) gene expression. The PMBL cell line MedB-1 shares many characteristic properties of the primary tumour, including low-level Ig production despite a functionally rearranged IgVH gene and absence of 'crippling' mutations. In this study, a search was undertaken for reasons for downregulated Ig expression. Similar levels of the B-cell-specific transcription factors BOB.1/OBF.1 and PU.1 were found in MedB-1 cells to those in the Ig-producing UM-1 lymphoblastoid cell line. However, MedB-1 lacked the Oct2 transcription factor. Reporter assays showed that Ig-type promoters were active in MedB-1 cells. In contrast, activity of the intronic heavy chain enhancer was dramatically reduced. Ectopic expression of Oct2 was able partially to restore enhancer activity but transcription from the endogenous IgVH gene could not be rescued. Therefore, the role of epigenetic factors in the downregulation of Ig was investigated. Methylated histone 3 lysine 9, a reliable marker of chromatin silencing, was not detected in MedB-1 promoter and enhancer regions. Inhibition of DNA methyltransferase and of histone deacetylases also did not reactivate Ig production. These data suggest the existence of alternative mechanisms of Ig inhibition in MedB-1 cells, different from chromatin silencing and the lack of Oct2.
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PMID:Downregulation of internal enhancer activity contributes to abnormally low immunoglobulin expression in the MedB-1 mediastinal B-cell lymphoma cell line. 1568 41

Several clinically relevant molecular classifiers of diffuse large B-cell lymphoma (DLBCL) have recently been demonstrated in Western populations. However, substantial molecular differences have recently been shown between tumors derived from different ethnic groups. To investigate prevalence and interrelationship of recently suggested molecular prognostic markers in Middle East DLBCL, we analyzed coexpression of CD10/Bcl6 (by immunohistochemistry), t(14;18) translocations (by fluorescence in situ hybridization), and methylation of the gene encoding the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) in a series of 190 DLBCL patients from Saudi Arabia with clinical follow-up data. Coexpression of CD10/Bcl6 (germinal center-like immunophenotype) was found in 13%, t(14;18) translocations in 17.9%, and MGMT methylation in 75.9% of cases. There was a trend toward better prognosis (although statistically insignificant) in tumors with coexpression of CD10/Bcl6. MGMT methylation were significantly related to good prognosis. The combined analysis of both parameters revealed that MGMT methylation was independent of immunophenotype and remained a significant predictor of prognosis in nongerminal center-like DLBCL subgroup. t(14;18) was significantly associated with CD10/Bcl6 coexpression (46.7%) but infrequent in CD10-/Bcl6-negative lymphomas (9.4%; P = .0073). However, t(14;18) was unrelated to clinical outcome. In summary, our data suggest a strong prognostic importance of MGMT methylation independent of DLBCL immunophenotype. Based on previous data from Western patients, the rate of MGMT hypermethylation was higher, and the portion of germinal center-like DLBCL was lower than expected. These results provide evidence for molecular differences between Saudi Arabian and Western DLBCL.
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PMID:High frequency and strong prognostic relevance of O6-methylguanine DNA methyltransferase silencing in diffuse large B-cell lymphomas from the Middle East. 1673 16

Glutathione-S-transferase P1 (GSTP1) and O6-methylguanine DNA methyltransferase (MGMT) are involved in drug-resistant to chemotherapeutic agents such as doxorubicin. In this study, prognostic significance of promoter hypermethylation and mRNA and protein expression of GSTP1 and MGMT together with promoter hypermethylation of death-associated protein kinase (DAPK) in diffuse large B cell lymphoma (DLBCL) was analyzed. Fifty-three patients with DLBCL, 24 men and 29 women, with age ranging from 23 to 91 (median 65), were analyzed. Genomic DNA and total RNA extracted from frozen samples of DLBCL were analyzed by methylation-specific polymerase chain reaction and quantitative reverse transcription polymerase chain reaction (RT-PCR) to determine promoter hypermethylation and mRNA expression of GSTP1, MGMT, and DAPK. Immunohistochemical analysis was performed to determine GSTP1 and MGMT expression at the protein level. Promoter hypermethylation of GSTP1, MGMT, and DAPK was detected in 12 (22.6%), 21 (39.6%), and 36 (67.9%) of 53 patients, respectively. Quantitative RT-PCR and immunohistochemistry did not show a correlation between methylation status and mRNA and protein expression of GSTP1 and MGMT. Patients with GSTP1 promoter hypermethylation showed a better 5-year overall survival rate than those without (100 vs 62.2%; p < 0.05). However, GSTP1 promoter hypermethylation was not an independent prognosticator in multivariate analysis. Methylation status of GSTP1 could be an indicator of drug response and a prognosticator for DLBCL.
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PMID:Correlation between promoter hypermethylation of GSTP1 and response to chemotherapy in diffuse large B cell lymphoma. 1750 13

The prognostic significance of O6-methylguanine DNA methyltransferase (MGMT) inactivation was evaluated in patients with diffuse large B-cell lymphoma (DLBCL) who received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in addition to rituximab. In this retrospective study, we used the methylation-specific polymerase chain reaction to investigate MGMT promoter methylation status and immunohistochemistry to evaluate MGMT expression in patients with DLBCL who received rituximab plus CHOP (R-CHOP) chemotherapy. No difference in patient characteristics, disease characteristics, response, or survival in patients with DLBCL who received front-line R-CHOP chemotherapy was observed according to MGMT methylation status and MGMT expression. On multivariate analysis, Grade 3-4 mucositis in the MGMT methylated group was significantly higher than that in the MGMT unmethylated group (hazard ratio (HR) 2.40, 95% CIs: 1.26-7.26, p = 0.014). This study demonstrated that inactivation of MGMT does not appear to play an important role in patients with DLBCL who received R-CHOP chemotherapy either with regard to the response rate or overall survival. Additionally, Grade 3-4 mucositis was found to be significantly related with inactivation of MGMT by a multivariate analysis.
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PMID:Is inactivation of O6-methylguanine DNA methyltransferase still a favorable prognostic factor of patients with diffuse large B-cell lymphoma in the era of R-CHOP chemotherapy? 1986 Jun 20

Epigenetic changes are among the most common alterations observed in cancer cells, yet the mechanism by which cancer cells acquire and maintain abnormal DNA methylation patterns is not understood. Cancer cells have an altered distribution of DNA methylation and express aberrant DNA methyltransferase 3B transcripts, which encode truncated proteins, some of which lack the COOH-terminal catalytic domain. To test if a truncated DNMT3B isoform disrupts DNA methylation in vivo, we constructed two lines of transgenic mice expressing DNMT3B7, a truncated DNMT3B isoform commonly found in cancer cells. DNMT3B7 transgenic mice exhibit altered embryonic development, including lymphopenia, craniofacial abnormalities, and cardiac defects, similar to Dnmt3b-deficient animals, but rarely develop cancer. However, when DNMT3B7 transgenic mice are bred with Emicro-Myc transgenic mice, which model aggressive B-cell lymphoma, DNMT3B7 expression increases the frequency of mediastinal lymphomas in Emicro-Myc animals. Emicro-Myc/DNMT3B7 mediastinal lymphomas have more chromosomal rearrangements, increased global DNA methylation levels, and more locus-specific perturbations in DNA methylation patterns compared with Emicro-Myc lymphomas. These data represent the first in vivo modeling of cancer-associated DNA methylation changes and suggest that truncated DNMT3B isoforms contribute to the redistribution of DNA methylation characterizing virtually every human tumor.
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PMID:DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis. 2058 27

During the past decade we have witnessed a number of changes in the field of non-Hodgkin lymphoma (NHL), including new entities added to the classification as well as a better understanding of the biology of diffuse large B-cell lymphoma (DLBCL). An understanding of the epigenetics of NHL is also contributing new agents for the management of this disorder. It has become increasingly clear that DLBCL is a biologically and clinically heterogeneous cell type. Two major categories are now recognized: germinal center B cell and activated B-cell (ABC) types. The former is associated with a good prognosis while the latter is known to have a more adverse outcome. With the use of routine immunohistochemical stains, these two types can be identified. The ABC type is known to be NFK-B dependent. NFK-B is a therapeutic target for bortezomib which is being investigated as treatment for this subtype of DLBCL. Several major changes in the classification will be discussed among which the most important are the recognition of so-called borderline entities. One of the two most common of these is the borderline DLBCL/Burkitt tumor (DLBCL/BL) which has features of both DLBCL and Burkitt's lymphoma. Many of the cases in this DLBCL/BL category contain a translocation of MYC as well as BCL2, so-called "double-hit lymphomas" which have a very aggressive clinical behavior. The second common borderline entity is the mediastinal grey zone NHL (MGZL) which has pathological features intermediate between primary mediastinal B-cell lymphoma and nodular sclerosing Hodgkin lymphoma (NSHL). Overlapping clinical features include young age, male predominance, and localized mediastinal presentation. Anecdotal reports suggest MGZL is relatively resistant to Hodgkin-based chemotherapy. Epigenetic therapy represents a new concept. Histone deacetylase inhibitors (HDACi)and DNA methyltransferase inhibitors constitute a promising new class of antineoplastic agents. They modify the expression of genes related to cancer development. In this review, we discuss the role of HDACi in lymphomagenesis as well as in treatment. To understand the benefits of HDACi in lymphoma treatment, we must appreciate the crucial interplay between BCL6, p53, and STAT3. The STAT3 oncogene is involved in the ABC type of DLBCL, an unfavorable and frequently therapy-refractory lymphoma. STAT3 can be effectively suppressed by several HDACi. We will summarize the results of recent trials with HDACi such as romidepsin, panobinostat and valproic acid that have shown significant preliminary activity in recurrent and refractory lymphomas. Their future role in front-line management remains to be determined.
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PMID:Non-Hodgkin's lymphoma: the old and the new. 2203 56

Protein tyrosine phosphatases such as PTPN6 can be downregulated in various neoplasms. PTPN6 expression by immunohistochemistry in 40 diffuse large B-cell lymphoma (DLBCL) tumors was lost or suppressed in 53% (21/40). To elucidate the molecular mechanisms of PTPN6 suppression, we performed a comprehensive epigenetic analysis of PTPN6 promoter 2 (P2). None of the DLBCL primary tumors (0/37) had PTPN6 hypermethylation on the CpG1 island using methylation-specific PCR, pyrosequencing, and high-resolution melting assays. However, hypermethylation in 57% (21/37) of cases was found in a novel CpG island (CpG2) in P2. PTPN6 gene suppression was reversed by 5-aza-deoxycytidine (5-Aza), a DNA methyltransferase inhibitor, and the histone deacetylase inhibitor (HDACi) LBH589. LBH589 and 5-Aza in combination inhibited DLBCL survival and PTPN6 hypermethylation at CpG2. The role of histone modifications was investigated with a chromatin-immunoprecipitation assay demonstrating that PTPN6 P2 is associated with silencing histone marks H3K27me3 and H3K9me3 in DLBCL cells but not normal B cells. 3-Deazaneplanocin A, a histone methyltransferase inhibitor, decreased the H3K27me3 mark, whereas HDACi LBH589 increased the H3K9Ac mark within P2 resulting in re-expression of PTPN6. These studies have uncovered novel epigenetic mechanisms of PTPN6 suppression and suggest that PTPN6 may be a potential target of epigenetic therapy in DLBCL.
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PMID:Epigenetic mechanisms of protein tyrosine phosphatase 6 suppression in diffuse large B-cell lymphoma: implications for epigenetic therapy. 2397 23

The pathogenesis of diffuse large B-cell lymphoma (DLBCL) is strongly linked to perturbation of epigenetic mechanisms. The germinal center (GC) B cells from which DLBCLs arise are prone to instability in their cytosine methylation patterns. DLBCLs inherit this epigenetic instability and display variable degrees of epigenetic heterogeneity. Greater epigenetic heterogeneity is linked with poor clinical outcome. Somatic mutations of histone-modifying proteins have also emerged as a hallmark of DLBCL. The effect of these somatic mutations may be to disrupt epigenetic switches that control the GC phenotype and "lock in" certain oncogenic features of GC B cells, resulting in malignant transformation. DNA methyltransferase and histone methyltransferase inhibitors are emerging as viable therapeutic approaches to erase aberrant epigenetic programming, suppress DLBCL growth, and overcome chemotherapy resistance. This review will discuss these recent advances and their therapeutic implications.
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PMID:The epigenetic basis of diffuse large B-cell lymphoma. 2580 88

Aberrant promoter hypermethylation resulting in the epigenetic silencing of apoptosis-associated genes is a key process in the chemotherapeutic treatment of cancer. The nucleoside analog, 5-aza-2'deoxycytidine (DAC), inhibits the activity of DNA methyltransferase enzymes and is able to restore the expression levels of genes that have been silenced by aberrant DNA methylation. The aim of the present study was to investigate the effect of combined treatment with DAC and cisplatin (CDDP) on the lung adenocarcinoma cell line, P15. Growth inhibition was examined using a clone formation assay and growth inhibitory activities by cell counting during treatment with DAC alone, CDDP alone or DAC followed by CDDP. In addition, changes in the mRNA expression levels of various apoptosis-associated genes following treatment with increasing concentrations of DAC were determined using reverse transcription-polymerase chain reaction. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis was used to detect the number of apoptotic P15 tumor cells following treatment with DAC and/or CDDP. The results indicated that DAC treatment alone restored the mRNA expression levels of p73, p16^INK4a , B-cell lymphoma (Bcl)-2-associated agonist of cell death and Bcl-2-associated X protein. In addition, combined therapy with DAC and CDDP was found to significantly suppress the growth of P15 tumor cells compared with DAC or CDDP treatment alone. In conclusion, DAC may enhance the chemosensitivity of the P15 cell line to treatment with CDDP.
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PMID:Effect of combined 5-aza-2'deoxycytidine and cisplatin treatment on the P15 lung adenocarcinoma cell line. 2613 3

The aims of the present study were to elucidate the transcript levels of DNA methyltransferase (DNMT)1, DNMT3a and DNMT3b by quantitative polymerase chain reaction in patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL), and determine the association of their expression with the clinical parameters and prognostic values of the disease. The results revealed that the expression of DNMT1 in patients with PGI-DLBCL was significantly higher than that in healthy controls (P=0.04), while the expression of DNMT3a and DNMT3b were significantly lower (P<0.001 and P=0.001, respectively). The increased expression of DNMT1 was significantly correlated with shorter overall survival and progression-free survival rates (P=0.018 and P=0.008, respectively). The multivariate analysis demonstrated that the level of DNMT1 was an independent prognostic factor. In conclusion, DNMT1 was identified to be an independent prognostic factor for predicting the survival of patients with PGI-DLBCL; this suggests that it could be used as a marker to indicate the prognosis of PGI-DLBCL.
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PMID:Overexpression of DNA methyltransferase 1 as a negative independent prognostic factor in primary gastrointestinal diffuse large B-cell lymphoma treated with CHOP-like regimen and rituximab. 2613 62

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