Identification of Candidate Tumor Suppressor Genes Silenced Epigenetically in Mantle Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3001-3001
Author(s):  
Norihiko Kawamata ◽  
Takayuki Saitoh ◽  
Sakura Sakajiri ◽  
Phillip H. Koeffler
Keyword(s):  
Tumor Suppressor ◽  
Mantle Cell Lymphoma ◽  
Real Time ◽  
Real Time Pcr ◽  
Tumor Suppressor Genes ◽  
Cell Lymphoma ◽  
Suppressor Genes ◽  
Expression Levels ◽  
Candidate Tumor Suppressor ◽  
Mantle Cell

Abstract Many tumor suppressor genes are silenced by epigenetic mechanisms in human cancers, including mantle cell lymphoma (MCL). In this study, we have used a variety of research tools to screen for genes that are epigenetically silenced in MCL. Changes in the global gene expression profile of the MCL cell line, Jeko1, were analyzed after treatment with the combination of the demethylating agent, 5-aza-2′-deoxycytidine, and the histone deacetylase inhibitor, suberoyl anilide bishydroxamide, by DNA microarray technique. By screening over 22,000 genes, we identified 26 candidate tumor suppressor genes, expression of which were enhanced by the treatment, in the MCL line. Basal expression of these 26 genes were low in Jeko1 cells. The treatment enhanced the expression more than 2 folds and the enhancement was also confirmed by real-time PCR. Methylation status of these 26 genes were examined by bisulfite sequencing and/or combined bisulfite and restriction enzyme digestion assay in Jeko1 cells. We found hypermethylation of a CpG island in the middle of the INPP5F gene. We also found the hypermethylation of that region of INPP5F in normal peripheral blood. We also examined expression levels of these 26 genes in normal mantle cells by real-time PCR and found only 11 genes showed high levels of transcription in laser-dissected normal mantle cells. We examined expression of these 11 genes in eight MCL clinical samples by real-time PCR and found that only three genes, INPP5F, DUSP10 and FGD2 showed very low expression levels. We conclude that expression of INPP5F, DUSP10 and FGD2 genes were suppressed in MCL cells although the expression of these genes are high in normal mantle cells. INPP5F is a inositol phosphatase and could be involved in PI3K pathway. DUSP10 is a dual specific phosphatase and could be involved in JNK pathway. FGD2 is a RAS-GAP gene and could be involved in RAS pathway. These three genes may be candidate tumor suppressor genes in MCL and further functional analysis is ongoing.

Antagonizing inactivated tumor suppressor genes and activated oncogenes by a versatile transgenesis system: application in mantle cell lymphoma

2006 ◽  
Vol 20 (8) ◽  
pp. 1188-1190 ◽  
Author(s):  
Armin Pscherer ◽  
Julia Schliwka ◽  
Kathrin Wildenberger ◽  
Antoaneta Mincheva ◽  
Carsten Schwaenen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Mantle Cell Lymphoma ◽  
System Application ◽  
Tumor Suppressor Genes ◽  
Cell Lymphoma ◽  
Suppressor Genes ◽  
Mantle Cell

Cyclin D1 (CCND1) messenger RNA expression as assessed by real-time PCR contributes to diagnosis and follow-up control in patients with mantle cell lymphoma

2013 ◽  
Vol 41 (12) ◽  
pp. 1028-1037 ◽  
Author(s):  
Ulrike Bacher ◽  
Wolfgang Kern ◽  
Claudia Haferlach ◽  
Tamara Alpermann ◽  
Torsten Haferlach ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Real Time ◽  
Real Time Pcr ◽  
Messenger Rna ◽  
Cell Lymphoma ◽  
Rna Expression ◽  
Mantle Cell

scholarly journals CyclinD1/CyclinD3 Ratio by Real-Time PCR Improves Specificity for the Diagnosis of Mantle Cell Lymphoma

2004 ◽  
Vol 6 (2) ◽  
pp. 84-89 ◽  
Author(s):  
Carol D. Jones ◽  
Katherine H. Darnell ◽  
Roger A. Warnke ◽  
James L. Zehnder
Keyword(s):  
Mantle Cell Lymphoma ◽  
Real Time ◽  
Real Time Pcr ◽  
Cell Lymphoma ◽  
Mantle Cell

scholarly journals Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 271-280 ◽  
Author(s):  
Cinta Mestre-Escorihuela ◽  
Fanny Rubio-Moscardo ◽  
Jose A. Richter ◽  
Reiner Siebert ◽  
Joan Climent ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
B Cell ◽  
Tumor Suppressor Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Promoter Hypermethylation ◽  
Homozygous Deletion ◽  
Suppressor Genes ◽  
Mantle Cell ◽  
Homozygous Deletions

Abstract Integrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Notably, the pattern of genetic and epigenetic inactivation differed among B-NHL subtypes. Thus, the P53-inducible PIG7/LITAF was silenced by homozygous deletion in primary mediastinal B-cell lymphoma and by promoter hypermethylation in germinal center lymphoma, the proapoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the proapoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma, and INK4c/P18 was silenced by biallelic mutation in mantle-cell lymphoma. Our microarray strategy has identified novel candidate tumor suppressor genes inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes.

Epigenetic Determinants of Pathogenesis and Resistance to Proteosome Inhibition in Mantle Cell Lymphoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3373-3373 ◽  
Author(s):  
Tobias Gellen ◽  
Pei-Yu Kuo ◽  
Rita Shaknovich ◽  
Maria E Figueroa ◽  
Ari Melnick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factor ◽  
Tumor Suppressor ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Tumor Suppressor Genes ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
Hypermethylated Genes

Abstract Mantle Cell Lymphoma (MCL) is an aggressive tumor accounting for 5% of non Hodgkin’s lymphomas(NHL). Given the poor clinical outcomes in this disease with current therapy, it is of great importance to better understand disease pathogenesis. Since aberrant epigenetic gene regulation is a hallmark of cancer, we hypothesized that an unbiased genome-wide DNA methylation study would identify genes involved in MCL pathogenesis. Moreover, we hypothesized that aberrantly silenced/hypermethylated genes responsible for drug sensitivity in MCL could be pharmacologically manipulated for maximizing clinical benefit. To address these questions, we examined the abundance of DNA methylation in 25,000 promoter fragments using the HELP (HPA II Enzyme Ligation mediated PCR amplification) assay in MCL cell lines. This study revealed s substantial heterogeneity in genomic methylation between cell lines, possibly reflective of underlying biologic diversity in this disease. However, MCL cell lines did display consistent aberrant methylation when compared to naïve B cells extracted from normal human tonsils. Remarkably, among the 102 genes with a methylation fold change in >3 and p<0.0001 the majority (100) were hypermethylated in MCL vs. normal B cells. Amongst these genes we identified five tumor suppressor genes implicated in the pathogenesis of other cancers: Protocadherin 8,Paternally expressed gene 3 (PEG3),Myeloid leukemia factor 1, Transcription Factor AP-2 gamma and Homeobox D8. Interestingly. PEG3 and Protocadherin 8 are both known to be silenced by hypermethylation at their gene promoters in gastric and breast cancer respectively. These genes may also possibly function as tumor suppressor genes in MCL pathogenesis and are excellent candidates for future functional studies. We then integrated methylation and gene expression data to identify loci that were both significantly methylated and suppressed in MCL. To identify the pathways and biological processes most relevant to our data set of methylated genes, we queried the Ingenuity Pathway Analysis (IPA) Knowledge base with the top 560 hypermethylated genes (>2 Standard Deviation) across all MCL cell lines. An unsupervised core analysis from the IPA knowledge base using our gene set revealed gene networks revolving around tumor suppressor TP53 and the NPM1 transcription factor in MCL cell lines. Locus specific confirmation by MassArray confirmed methylation of the distal portion of the TP53 promotor in the MCL cell lines. Recently, the proteosome inhibitor Bortezomib(BZM) has been shown to have specific activity in MCL, with single agent response rates ~40% in heavily pretreated patients. We wondered whether aberrant epigenetic programming might contribute to resistance to this agent and whether reversal of DNA methylation could overcome cellular mechanisms of resistance to Bortezomib. Therefore, to determine whether pharmacologic re-expression of genes could overcome bortezomib resistance, we treated MINO (a Bortezomib-refractory MCL cell line) with two low doses of Decitabine (0.1 uM and 1 uM) for 48 hours and sequentially with 15 nM of Bortezomib (IC50) for an additional 48 hours. Pretreatment of BZM-resistant MINO cells with Decitabine significantly (p<0.001) reduced cell viability as compared to control, suggesting that Decitabine can overcome BZM resistance in this refractory cell line. We are currently determining which genes contribute to this effect and validating these results in patient samples from a prospective trial of BZM+EPOCH. We predict that this will provide the basis for future trials individualizing BZM based therapy based on methylation and gene expression signatures in MCL.

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