Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology and pathogenesis of Hodgkin lymphoma (HL) are not yet known. There are implications of genes involved in programmed cell death (apoptosis), and there have been repeated suggestions of an association with Epstein-Barr virus (EBV). The aim of this study was to investigate the protein expression patterns of key cell cycle-related genes, together with evidence of apoptosis and EBV status, in relation to clinical stage in HLs. A double immunohistochemical and in situ hybridization technique was used to detect the expression of bcl-2, p53, retinoblastoma (Rb), p21, Ki67 (MIB 1), and topoisomerase IIalpha (TopoIIalpha), together with latent membrane protein-1 and EBER for EBV status and TdT-mediated dUTP-FITC nick end-labeling (TUNEL) as a measure of apoptosis, on tissue microarray sections of 62 cases of classic HL (35 NS, 17 MC, 8 LR, and 2 LD). A panel of phenotypic markers was used to facilitate recognition of Hodgkin and Reed-Sternberg (H-RS) cells: CD3, CD20, CD30, CD15, and EMA. The H-RS cells of 62 classic Hodgkin lymphomas were bcl-2-positive in 35 cases (56.45%), p53-positive in 14 (22.58%), and positive for both EBV latent membrane protein-1 and EBER in 37 (59.68%); there was complete concordance of results for EBV by both procedures. No correlation was found between expression of bcl-2, p53, or EBV markers in H-RS cells and clinical stage (P > 0.05). Expression of Rb, Ki67, p21, and TopoIIalpha did, however, show significant differences with clinical stage. Expression of Rb and p21 in CD30-positive H-RS cells decreased with more advanced stage (P < 0.001). In contrast, Ki67 and ToPoIIalpha expression increased with later stage (P < 0.01). No correlation was found between expression of any of these markers in H-RS cells and the subtypes of nodular sclerosis HL, mixed cellularity HL, and LRHL (P > 0.05). TUNEL was found in the nonneoplastic cellular background in all cases and in H-RS cells in only 10 of 62 cases (16.12%) (8 nodular sclerosis HL, 1 mixed cellularity HL, and 1 LRHL). There was a significant correlation between high expression of bcl-2 and a low score by TUNEL (P < 0.05). These data are consistent with the notion that overexpression of bcl-2 may be linked to blockage of apoptosis-mediated death of H-RS cells in classic HL. Abnormal expression of p53-related protein may not play a major role in HL, because it is present in H-RS cells in only a minority of cases. Increased expression of Ki67 and TopoIIalpha by H-RS cells is significantly associated with advanced stage and may indicate aggressive disease. Adverse clinical outcome in HL also is associated with loss of Rb and p21 protein expression, consistent with the possible roles of Rb and p21 in inhibition of the growth of H-RS cells. Within the limitations of the methods used, almost two thirds of cases of HL provide evidence of an association with EBV. The tissue microarray technique is valuable not only for examination of large numbers of cases of a disease by a complex panel of markers but also potentially as a control for staining quality in immunohistochemistry and in situ hybridization.
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PMID:Apoptosis and cell cycle-related genes and proteins in classical Hodgkin lymphoma: application of tissue microarray technique. 1296 46

Recently, comparative genomic hybridization (CGH)- and fluorescence in situ hybridization (FISH)-analyses of native Hodgkin and Reed-Sternberg (H&RS) cells extracted from Hodgkin lymphoma (HL) revealed a recurrent amplification of the HDM2 locus on chromosome 12. HDM2 is known to target, inactivate and to degrade p53. Wild type (wt) p53 protein is detected in high levels in HL. Simultaneously, stabilized wt p53 and spliced hdm2 transcripts have been observed in different tumors. Therefore, we examined the expression and structure of HDM2 in HL cell lines and possible effects on components of the p53 pathway. DNA integrity and induction potential of p53 was verified by DNA sequencing and detection of potential effector proteins (p21(WAF/CIP), HDM2) using immunofluorescence, respectively. All HL cell lines show an overexpression of HDM2 protein. Furthermore, several different spliced hdm2 transcripts (mdm-sv) including five new variants lacking a functional p53 binding site were characterized. If expressed, corresponding proteins were shown to be not restricted to the nucleus. Co-localization of the potential binding partners HDM2/p14(ARF) and HDM2/p53 was found in HL cell lines. We suggest that HDM2-sv have no significant disturbing influence on the interaction of these proteins.
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PMID:Abundant expression of spliced HDM2 in Hodgkin lymphoma cells does not interfere with p14(ARF) and p53 binding. 1456 63

Richter's transformation denotes the development of high-grade non-Hodgkin lymphoma, prolymphocytic leukemia, Hodgkin disease, or acute leukemia in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. A search of published articles in Medline (PubMed) and abstracts from professional meetings was performed. An electronic database search of patients with CLL at The University of Texas M. D. Anderson Cancer Center (Houston, TX) determined the incidence of Richter syndrome (RS) in patients with CLL between 1992 and 2002. RS occurs in approximately 5% of patients with CLL. The large cells of RS may arise through transformation of the original CLL clone or represent a new neoplasm. RS may be triggered by viral infections, such as Epstein-Barr virus. Trisomy 12 and chromosome 11 abnormalities are more frequent in patients with RS than in the overall population of patients with CLL. Multiple genetic defects, such as mutations of the p53 tumor suppressor gene, p16INK4A, and p21, loss of p27 expression, deletion of retinoblastoma, increased copy number of C-MYC, and decreased expression of the A-MYB gene, have been described. These abnormalities may cause CLL cells to proliferate and-by facilitating the acquisition of new genetic abnormalities-to transform into RS cells. Therapeutic strategies include intensive chemotherapy, monoclonal antibodies, and stem cell transplantation. The response rates range from 5% to 43% (complete response, 5-38%), and the median survival duration ranges from 5 months to 8 months. In conclusion, RS may be triggered by viral infections or by genetic defects. Current treatments are aggressive, but prognosis is poor. Novel curative treatment strategies are needed.
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PMID:Richter syndrome: biology, incidence, and therapeutic strategies. 1557 83

The HDM2 oncoprotein is a cellular inhibitor of p53 and is frequently deregulated in human cancer. However, the HDM2 gene encodes alternatively spliced variants whose functional significance is poorly understood. We had previously reported the detection of alternative HDM2 forms in Hodgkin's lymphoma (HL)-derived cell lines. Here, we have cloned several of these transcripts, including the previously described HDM2-A, -B and -C (which encode the COOH terminus of HDM2), and two novel variants (HDM2-HL1 and -HL2) containing a complete p53 interaction domain. Real-time PCR assays demonstrated that HDM2-A and -B were selectively expressed by HL cell lines and primary tumors, compared with their non-neoplastic counterparts. In transient transfection experiments, alternatively spliced HDM2 isoforms were partially or totally localized within the cytoplasm. HDM2-HL2 was able to inhibit transactivation of a p53-inducible reporter construct and induced a partial relocalization of p53 to the cytoplasm. Expression of HDM2-A and -B caused the activation of p53/p21 and induced growth arrest in primary cells, but also increased the expression levels of cyclins D1 and E. Other possible genes regulated by HDM2-A and -B were identified using cDNA microarray technology. These results imply that HDM2 isoforms may have multiple effects on cell cycle control, and provide insight into the mechanisms through which these molecules contribute to tumorigenesis.
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PMID:Hodgkin's lymphoma cells express alternatively spliced forms of HDM2 with multiple effects on cell cycle control. 1633 Dec 55

Primary effusion lymphoma, a peculiar type of B cell non-Hodgkin lymphoma, preferentially develops in immunodeficient individuals and its pathogenesis is closely linked with human herpesvirus 8 (HHV-8). HHV-8 is present primarily persistence in primary effusion lymphoma cells, and the lytic cycle of HHV-8 can be induced by sodium butyrate (NaB) treatment. HHV-8 gene expression is affected by NaB in BCBL-1 cells, but the cellular response of BCBL-1 cells upon NaB treatment has not been investigated to date. Using BCBL-1 cells, a HHV-8 harboring cell line, we demonstrated that sodium butyrate could induce the reactive oxygen species generation, apoptosis and cell cycle arrest in BCBL-1 cells. The sodium butyrate-induce cell cycle arrest was associated with the decrease of Cdc2, Cdk4 and cyclin A in BCBL-1 cells without altering the protein levels of p21(CIP1/WAF1). The apoptosis induced by sodium butyrate in BCBL-1 cells was independent of oxidative stress.
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PMID:Sodium butyrate induces apoptosis and cell cycle arrest in primary effusion lymphoma cells independently of oxidative stress and p21(CIP1/WAF1) induction. 1647 79

Aims-To investigate the pattern of expression of p53 protein and two wild type p53 induced proteins (mdm2 and p21/waf1) as an indirect way of assessing p53 gene status in non-Hodgkin's lymphoma.Methods-Formalin fixed, paraffin wax embedded tissue from 87 cases of nodal non-Hodgkin's lymphoma, comprising 52 high grade and 35 low grade tumours, was stained by immunohistochemistry for p53, mdm2 and p21/waf1 proteins.Results-p53, mdm2 and waf1/p21 proteins were expressed in 36/52, 21/52 and 31/52 high grade and 3/35, 21/35 and 3/35 low grade non-Hodgkin's lymphomas, respectively. Parallel p53/mdm2 protein expression was found in 23 cases (21 high grade and two low grade). These 23 cases were also positive for p21/waf1 protein expression. Discordant p53 positive/mdm2 negative protein expression was found in 16 cases (15 high grade and one low grade). Eleven (10 high grade and one low grade) of these 16 cases were p21/waf1 positive and the remaining five high grade non-Hodgkin's lymphomas were p21/waf1 negative. Mdm2 and p21/waf1 proteins were not expressed in the absence of p53 protein expression.Conclusions-p53, mdm2 and waf1/p21 protein expression is more frequently associated with aggressive histotypes of non-Hodgkin's lymphoma. Parallel expression of p53, mdm2 and p21 proteins may represent non-Hodgkin's lymphomas with a wild type p53 gene as mdm2 and p21 proteins can be induced by the wild type gene. In these cases p53 protein expression may result from stabilisation via complex formation with the mdm2 protein. This could be important in the pathogenesis of these cases as mdm2 may deregulate the p53 dependent growth suppressive pathway. Discordant p53 positive/mdm2 negative/p21 negative protein expression may represent non-Hodgkin's lymphoma with p53 gene mutations unable to activate expression of mdm2 and p21 proteins. Non-Hodgkin's lymphoma with p53 positive/mdm2 negative/p21 positive protein expression may have either wild type p53 with deregulated mdm2 gene expression or mutated p53 gene with p53 independent p21 expression.
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PMID:p53 protein expression in non-Hodgkin's lymphoma. Comparative study with the wild type p53 induced proteins mdm2 and p21/waf1. 1669 89

Inversions are infrequent events in hematological malignancies. We here report the cytogenetic, fluorescence in situ hybridization (FISH), and molecular studies of 2 patients diagnosed with mantle cell lymphoma (MCL) that showed inversions of chromosomes 2 and 6 as part of complex karyotypes. Both patients showed a cytogenetically identical inv(6)(p23q11) detected as a secondary aberration. In addition, both patients had a derivative chromosome 2 which originated by partial deletion of the short arm and a pericentric inversion with different breakpoints on the long arm: der(2)del(2)(p21)inv(2)(p21q11) and der(2)del(2)(p21)inv(2)(p21q13), respectively. The presence of t(11;14)(q13;q32) was confirmed by interphase FISH and by molecular study. Residual normal cells were found in both cases. The patients showed a different clinical evolution with a poor outcome for one case and a favorable course of the disease for the other one. The review of the literature in MCL showed a total of 9 inversions affecting different chromosomes. Considering that inversions are very infrequent events in MCL, our findings could be important for detecting genes potentially involved in development and/or progression of this aggressive non-Hodgkin lymphoma subtype.
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PMID:Inversions of chromosomes 2 and 6 in mantle cell lymphoma. Cytogenetic, FISH, and molecular studies. 1673 18

In Argentina, lymphomas account for 13.6% of all pediatric tumors and 47% of them are Hodgkin lymphoma. Previous studies of lymphoma series have reported the expression of apoptotic and cell cycle proteins. Our aim was to study these markers in our pediatric patients and correlate them with their outcome. Immunohistochemical staining with monoclonal antibodies anti-p53, bcl-2, p21, and mdm2 were performed on formalin-fixed paraffin-embedded Hodgkin lymphoma lymph node biopsies from 54 pediatric patients. The analyzed oncogenes p53, bcl-2, p21, and mdm2 exhibited 81%, 44%, 76%, and 90% positive staining, respectively. The most prevalent p53/p21 expression pattern was p53+/p21+, in 57% of cases, whereas concerning p53/mdm2 expression pattern p53+/mdm2+ was observed in 61% of cases. We failed to find any statistically significant correlation between oncogene expression and patient's survival. It seems that p53 plays an important role in lymphomagenesis in our studied population, because it is overexpressed in 81% of Hodgkin lymphoma cases and in more than 50% of cases, it might be able to activate its cellular effectors. Bcl-2 staining observed in 44% of our cases could represent a failure in bcl-2 down-regulation that leads to a rescue event in defective germinal center B-cells, that allows them to develop into Reed-Sternberg and Hodgkin cells.
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PMID:No Influence of bcl-2, p53, and p21waf1 protein expression on the outcome of pediatric Hodgkin lymphomas. 1700 59

CD30 is a member of the tumor necrosis factor receptor superfamily whose expression is up-regulated on anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) cells. Many different outcomes of CD30 stimulation have been reported, including cell cycle arrest, apoptosis, and activation of the prosurvival transcription factor, NF-kappaB, although this last activity is much less well defined in ALCL cells. In order to better understand the signaling properties of CD30 in cancer, we established a system for the stimulation of CD30 with its physiological ligand. Using this system, CD30 was stimulated on ALCL and HL cells, and the subsequent CD30 signaling properties were characterized. We show that a fraction of ALCL cells rapidly underwent apoptosis following CD30 stimulation, whereas HL cells were unaffected. The surviving ALCL cells exhibited robust activation of both the canonical and alternative NF-kappaB pathways as measured by nuclear translocation of RelA, p50, RelB, and p52, and this culminated in the transactivation of classical NF-kappaB-responsive genes. With prolonged CD30 stimulation, ALCL cells underwent cell cycle arrest that correlated with expression of the cell cycle inhibitor p21(waf1). Furthermore, p21(waf1) expression and cell cycle arrest were found to depend predominantly on the canonical NF-kappaB pathway, since it was reversed by RNA interference-mediated suppression of RelA. In contrast, suppression of the p100/p52 NF-kappaB subunit had little effect on p21(waf1). These data reveal that in ALCL cells, in contrast to other cell types, CD30 stimulation elicits p21(waf1)-mediated arrest through the canonical but not the alternative NF-kappaB pathway.
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PMID:CD30 activates both the canonical and alternative NF-kappaB pathways in anaplastic large cell lymphoma cells. 1726 81

Mounting evidence suggests that dynamic interactions between a tumor and its microenvironment play a critical role in tumor development, cell-cycle progression, and response to therapy. In this study, we used mantle cell lymphoma (MCL) as a model to characterize the mechanisms by which stroma regulate cell-cycle progression. We demonstrated that adhesion of MCL and other non-Hodgkin lymphoma (NHL) cells to bone marrow stromal cells resulted in a reversible G(1) arrest associated with elevated p27(Kip1) and p21 (WAF1) proteins. The adhesion-mediated p27(Kip1) and p21 increases were posttranslationally regulated via the down-regulation of Skp2, a subunit of SCF(Skp2) ubiquitin ligase. Overexpression of Skp2 in MCL decreased p27(Kip1), whereas inhibition of Skp2 by siRNA increased p27(Kip1) and p21 levels. Furthermore, we found cell adhesion up-regulated Cdh1 (an activating subunit of anaphase-promoting complex [APC] ubiquitin ligase), and reduction of Cdh1 by siRNA induced Skp2 accumulation and hence p27(Kip1) degradation, thus implicating Cdh1 as an upstream effector of the Skp2/p27(Kip1) signaling pathway. Overall, this report, for the first time, demonstrates that cell-cell contact controls the tumor cell cycle via ubiquitin-proteasome proteolytic pathways in MCL and other NHLs. The understanding of this novel molecular pathway may prove valuable in designing new therapeutic approaches for modifying tumor cell growth and response to therapy.
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PMID:Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. 1750 56


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