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.

Analysis of the P53, RB/D13S25, and P16 Tumor Suppressor Genes in Marginal Zone B-cell Lymphoma

2000 ◽  
Vol 120 (1) ◽  
pp. 1-5 ◽  
Author(s):  
J Dierlamm ◽  
M Stefanova ◽  
I Wlodarska ◽  
K Hinz ◽  
B Maes ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
B Cell ◽  
Tumor Suppressor Genes ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Suppressor Genes

scholarly journals Inactivation of Tumor Suppressor Genes p15INK4b and p16INK4a in Primary Cutaneous B Cell Lymphoma

2002 ◽  
Vol 118 (6) ◽  
pp. 941-948 ◽  
Author(s):  
Fiona J. Child ◽  
Julia J. Scarisbrick ◽  
Robin Russell-Jones ◽  
Sean J. Whittaker ◽  
Eduardo Calonje ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
B Cell ◽  
Tumor Suppressor Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Suppressor Genes ◽  
Cutaneous B Cell Lymphoma

The prognostic impact of hypermethylation for a panel of tumor suppressor genes and cell of origin subtype on diffuse large B-cell lymphoma

2019 ◽  
Vol 46 (4) ◽  
pp. 4063-4076 ◽  
Author(s):  
Samir A. Shawky ◽  
Mohamed H. El-Borai ◽  
Hussein M. Khaled ◽  
Iman Guda ◽  
Marwa Mohanad ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
B Cell ◽  
Tumor Suppressor Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Cell Of Origin ◽  
Suppressor Genes ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Promoter Methylation of RASSF1A Associates to Adult Secondary Glioblastomas and Pediatric Glioblastomas

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Jorge Muñoz ◽  
María del Mar Inda ◽  
Paula Lázcoz ◽  
Idoya Zazpe ◽  
Xing Fan ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Lines ◽  
Tumor Suppressor Genes ◽  
Promoter Hypermethylation ◽  
Suppressor Genes ◽  
Primary Tumors ◽  
Specific Pcr ◽  
Inactivation Mechanism ◽  
Altered Gene ◽  
Homozygous Deletions

While allelic losses and mutations of tumor suppressor genes implicated in the etiology of astrocytoma have been widely assessed, the role of epigenetics is still a matter of study. We analyzed the frequency of promoter hypermethylation by methylation-specific PCR (MSP) in five tumor suppressor genes (PTEN, MGMT, RASSF1A, p14ARF, and p16INK4A), in astrocytoma samples and cell lines. RASSF1A was the most frequently hypermethylated gene in all grades of astrocytoma samples, in cell lines, and in adult secondary GBM. It was followed by MGMT. PTEN showed a slight methylation signal in only one GBM and one pilocytic astrocytoma, and in two cell lines; while p14ARF and p16INK4A did not show any evidence of methylation in primary tumors or cell lines. In pediatric GBM, RASSF1A was again the most frequently altered gene, followed by MGMT; PTEN, p14 and p16 showed no alterations. Lack or reduced expression of RASSF1A in cell lines was correlated with the presence of methylation. RASSF1A promoter hypermethylation might be used as a diagnostic marker for secondary GBM and pediatric GBM. Promoter hypermethylation might not be an important inactivation mechanism in other genes like PTEN, p14ARF and p16INK4A, in which other alterations (mutations, homozygous deletions) are prevalent.

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

MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes

Blood ◽  
2009 ◽  
Vol 113 (2) ◽  
pp. 396-402 ◽  
Author(s):  
Mika Inomata ◽  
Hiroyuki Tagawa ◽  
Yong-Mei Guo ◽  
Yoshihiro Kameoka ◽  
Naoto Takahashi ◽  
...  
Keyword(s):  
Cell Growth ◽  
B Cell ◽  
Cell Cycle Progression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Homozygous Deletion ◽  
Cycle Progression ◽  
P53 Expression ◽  
Proapoptotic Protein ◽  
Mantle Cell

Abstract Aberrant overexpression of the miR-17-92 polycistron is strongly associated with B-cell lymphomagenesis. Recent studies have shown that miR-17-92 down-regulates the proapoptotic protein Bim, leading to overexpression of Bcl2, which likely plays a key role in lymphomagenesis. However, the fact that Jeko-1 cells derived from mantle cell lymphoma exhibit both homozygous deletion of BIM and overexpression of miR-17-92 suggests other targets are also involved in B-cell lymphomagenesis. To identify essential target(s) of miR-17-92 in lymphomagenesis, we first transfected miR-17-92 into 2 genetically distinct B-cell lymphoma cell lines: Raji, which overexpress c-Myc, and SUDHL4, which overexpress Bcl2. Raji transfected with miR-17-19b-1 exhibited down-regulated expression of Bim and a slight up-regulation in Bcl2 expression. On the other hand, SUDHL4 transfectants showed aggressive cell growth reflecting facilitated cell cycle progression at the G1 to S transition and decreased expression of CDKN1A mRNA and p21 protein (CDKN1A/p21) that was independent of p53 expression. Conversely, transfection of antisense oligonucleotides against miR-17 and miR-20a into Jeko-1 led to up-regulation of CDKN1A/p21, resulting in decreased cell growth with G1 to S arrest. Thus, CDKN1A/p21 appears to be an essential target of miR-17-92 during B-cell lymphomagenesis, which suggests the miR-17-92 polycistron has distinct targets in different B-cell lymphoma subtypes.

MicroRNA-17-92 Downregulates Expression of Distinct Targets in Different B-Cell Lymphoma Subtypes

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5321-5321
Author(s):  
Hiroyuki Tagawa ◽  
Mika Inomata ◽  
Yong-Mei Guo ◽  
Yoshihiro Kameoka ◽  
Naoto Takahashi ◽  
...  
Keyword(s):  
Cell Growth ◽  
B Cell ◽  
Cell Cycle Progression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Homozygous Deletion ◽  
P53 Expression ◽  
Raji Cells ◽  
Apoptotic Protein ◽  
Mantle Cell

Abstract Aberrant overexpression of the miR-17-92 polycistron is strongly associated with B-cell lymphomagenesis. Recent studies have shown that miR-17-92 downregulates the pro-apoptotic protein Bim, leading to overexpression of Bcl2, which likely plays a key role in lymphomagenesis. However, the fact that Jeko-1 cells derived from mantle cell lymphoma exhibit both homozygous deletion of BIM and overexpression of miR-17-92 suggests other targets are also involved in B-cell lymphomagenesis. To identify essential target(s) of miR-17-92 in lymphomagenesis, we first transfected miR-17-92 into genetically distinct B-cell lymphoma cell lines, including Raji cells, which overexpress c-Myc, and SUDHL4 cells, which overexpress Bcl2. Raji cells transfected with miR- 17-19b exhibited downregulation of Bim and reversible upregulation of Bcl2. On the other hand, SUDHL4 cells transfected with miR-17-19b showed aggressive cell growth reflecting facilitated cell cycle progression at the G1-S transition, and decreased expression of CDKN1A mRNA and p21 protein (CDKN1A/p21) that was independent of p53 expression. Conversely, transfection of antisense oligonucleotides against miR-17 and miR-20a into Jeko-1 cells led to upregulation of CDKN1A/p21, resulting in decreased cell growth with G1-S arrest. Thus, CDKN1A/p21 appears to be an essential target of miR-17-92 during B-cell lymphomagenesis, which suggests the polycistron has distinct targets in different B-cell lymphoma subtypes.

Significance of Ubiquitin Ligase Subunit SKP-2 Proto-Oncogene and Proliferative Marker Ki67 Expression in Diffuse Large B-Cell Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4343-4343
Author(s):  
Shahab Uddin ◽  
Azhar R. Hussain ◽  
Prashant P. Bavi ◽  
Khawla S. Al-Kuraya
Keyword(s):  
Tumor Suppressor ◽  
Cytochrome C ◽  
B Cell ◽  
Expression Pattern ◽  
Ubiquitin Ligase ◽  
Tumor Suppressor Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract S-phase kinase-associated protein 2 (SKP-2) is a proto-oncogene that has been shown to be expressed in a number of tumors. A number of studies have shown that SKP-2 plays a role in the degradation of tumor suppressor genes by increased proteosome-dependent degradation. SKP-2 overexpression is highly representative of intrinsic biological aggressiveness of certain cancers including breast, non-small cell lung cancer and gastric carcinoma, how ever its role in hematological malignancies have not yet been explored. Therefore, in this study we examined 100 clinical samples of diffuse large B-cell lymphoma (DLBCL) to study the expression pattern of ubiquitin ligase subunit SKP-2 proto-oncogenes and its relation to proliferative index marker protein Ki67 to correlate tumor aggressiveness. The expression of SKP-2 and Ki67 were examined by immunohistochemistry using specific antibodies on formalin-embedded tissue sections of DLBCL patients. Our data showed that SKP-2 was over expressed in majority of DLBCL and was associated with expression pattern of the proliferating index marker Ki67 protein. Since increased proteosome-dependent degradation of tumor suppressor genes play a critical role in the etiology of various tumors and proteosome inhibition is a novel approach for treating malignancies and has been approved for clinical use, we sought to determine whether inhibition of proteosome by MG132, a specific proteosome inhibitor induces apoptosis in a panel of DLBCL cell lines. Our data showed that treatment of DLBCL cell lines by MG132 induced apoptosis in a dose dependent manner. Inhibition of proteosome also decreased the expression of SKP-2 leading to subsequent disruption of mitochondrial membrane potential causing release of cytochrome c into the cytosol. Release of cytochrome c resulted in activation of caspase-3 and cleavage of PARP ultimately leading to apoptosis. These data suggests that SKP-2 expression plays a major role in the oncogenesis of DLBCL and overexpression of SKP-2 can be used as useful prognostic marker. Furthermore, proteosome inhibitors can be used as future therapeutic modality in treating DLBCL.

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