Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Allelic deletions have been thought to be indicators of the presence of tumor suppressor genes (TSGs). As indicated by this allelotype study using 39 highly informative microsatellite markers distributed among all autosomal chromosomes, frequent loss of heterozygosity (LOH) has been found at 6p in B-cell non-Hodgkin's lymphoma. To identify the commonly deleted regions (CDRs), we performed fine deletion mapping using 26 highly polymorphic microsatellite markers on 6p. The most frequent LOH occurred at D651721, where 9 of 18 of the informative cases (50%) had allelic losses. Seventeen of 32 cases (53%) exhibited LOH at least at one locus on 6p. Ten of these 17 cases showed interstitial deletions, and their LOH patterns indicated two CDRs on 6p; one between D6S1721 and D6S260 (at 6p23-24), and the other between D6S265 and D6S291 (at 6p21). The genetic distance of both CDRs was 6 cM. The CDKN1A (p21) gene is reported to be located within the interval of the CDR at 6p21, but no mutation of the gene was found in these 32 patients. These data suggested that these two loci might harbor novel putative TSGs responsible for the pathogenesis of malignant lymphoma. We have constructed a contig of yeast artificial chromosome (YAC) clones spanning the most frequent CDR at 6p23-24. This YAC contig can be used for fine physical mapping of the region and cloning of candidate TSGs.
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PMID:Identification and mapping of novel tumor suppressor loci on 6p in diffuse large B-cell non-Hodgkin's lymphoma. 1037 74

Different studies have already shown that the isolated inactivation of p21, p16, or p27 cyclin-dependent kinase inhibitors (CKIs) is associated with increased growth fraction, tumor progression, or decreased overall survival in cases of non-Hodgkin's lymphoma. In this study we linked molecular study of the p53 and p16 genes with immunohistochemical analysis of p27 expression in a group of aggressive B-cell lymphomas [large B-cell lymphomas (LBCLs) and Burkitt's lymphomas]. This was done to analyze the relationship between p53 and p16 silencing, p27 anomalous overexpression, and clinical follow-up, testing the hypothesis that the accumulation of CKI alterations could confer to the tumors a higher aggressivity. In a group of 62 patients, p53 inactivation as a result of mutation was observed in 11 cases (18%) and p16 silencing was seen in 27 cases (43.5%) as a result of methylation (20 of 62), 9p21 deletion (7 of 44), or p16 mutation (2 of 62). The simultaneous inactivation of p53 and p16 was detected exclusively in five LBCL cases. Anomalous expression of p27, which has been proven to be associated with the absence of p27/CDK2 complexes and the formation of p27/cyclin D3 complexes where p27 is inactivated, was detected in 19 of 61 cases (31%). Cases characterized by p27 anomalous expression display concurrent inactivation of p21 (provided by p53 mutations) and/or p16 CKIs in 11 of 14 LBCL cases (P = 0.040). When the relationship between the association of inactivated CKIs and overall survival was considered, a significant relationship was found between a lower overall survival probability and an increased number of inactivated CKIs in LBCL cases, with the worst prognosis for the cases displaying concurrent p53, p16, and p27 alterations. This proves that simultaneous inactivation of different tumor suppressor pathways does indeed take place, and that tumor aggressiveness takes advantage of this CKI-concerted silencing. In this same series of data, Burkitt's lymphoma patients seem to behave in a different way than LBCLs, with p53 and p16 alteration being mutually exclusive and the association with p27 anomalous expression not being clinically significant. These facts seem to support that the additive effect of the inactivation of different CKIs could be dependent of the histological type.
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PMID:Overall survival in aggressive B-cell lymphomas is dependent on the accumulation of alterations in p53, p16, and p27. 1143 67

The BCL6 gene mapped at chromosome band 3q27 encodes a zinc-finger transcription factor and is frequently rearranged and deregulated in B-cell non-Hodgkin's lymphoma (NHL) by promiscuous chromosomal translocations which involve diverse genes. We identified a novel t(3;6)(q27;p21) in a follicular lymphoma (FL) with histologic evidence of transformation and, by cloning the translocation junction, determined that the SRP20 gene was the partner. In this translocation, the 5' regulatory region of the BCL6 was substituted by a putative regulatory region of SRP20. Previously, we hypothesized that substitution of BCL6 promoter by those of the partner genes that were constitutively expressed throughout B-cell development led to persistent and inappropriate expression of BCL6. We examined the expression pattern of SRP20 during B-cell development by Northern blot analysis of a panel of B-cell lines representing various stages of B-cell development and noted that SRP20 mRNA was expressed throughout B-cell development. The SRP20 gene plays an important role in regulation of pre-mRNA splicing, and is expressed specifically in lymphoid tissues. This study provides the first evidence of SRP20 gene rearrangement in human hematopoietic malignancies.
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PMID:Splicing factor SRP20 is a novel partner of BCL6 in a t(3;6)(q27;p21) translocation in transformed follicular lymphoma. 1157 68

Peripheral T-cell lymphomas (PTCL) are usually characterized by aggressive clinical behaviour and poor clinical outcome, but their biological background has not been extensively investigated to date, due to their low incidence, about 10% of all non-Hodgkin's lymphoma cases in Western countries, and also to the paucity of specific molecular-genetic abnormalities. Neverthless, there is increasing biological and clinical evidence that primary nodal PTCL should be considered separately from extra-nodal cases, but little is known about biological factors of possible clinical and prognostic impact. This immunohistochemical study has analysed the expression of p53, Mdm2, p21(WAF1), BCL-2 and p-glycoprotein (MDR-1 gene product) in a series of 45 cases of nodal peripheral T-cell lymphomas (PTCL) with 'high-grade' histology. The immunohistochemical findings were then correlated with proliferative activity and clinical outcome. p53 was over-expressed in 13 cases (28.9%). p53 positive cases showed significantly higher proliferative activity (p<0.01), more frequent expression of Bcl-2 (p<0.01) and less frequent expression of p21(WAF1) than p53 negative cases. Mdm2 and p-glycoprotein were expressed in 4/13 (30.8%) and 8/13 (61.5%) p53 positive cases respectively, and in none (0%) of the p53 negative cases (p<0.01). Analysis of the survival curves showed that p53 positive cases were associated with a significantly poorer clinical outcome than p53 negative cases, in terms of both overall survival (p=0.0032) and event-free survival (p=0.0004). Furthermore, multivariate analysis showed that p53 expression was the most important independent prognostic variable. These findings indicate that p53 over-expression identifies a subset of nodal PTCL cases with a distinctive biological profile (higher proliferative activity, less frequent expression of p21(WAF1) and more frequent expression of Bcl-2, Mdm2 and p-glycoprotein than p53 negative cases) and poor clinical outcome. The immunohistochemical analysis of p53 expression is a simple, rapid and low-cost method which may provide information of potential clinical and prognostic value in nodal peripheral T-cell lymphomas.
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PMID:p53 over-expression identifies a subset of nodal peripheral T-cell lymphomas with a distinctive biological profile and poor clinical outcome. 1167 35

Mantle cell lymphoma (MCL) is a distinct type of B-cell non-Hodgkin's lymphoma characterized by cyclin D1 overexpression and the cytogenetic abnormality, the t(11;14)(q13;q32). MCL cell lines have been difficult to establish and in vitro studies of these neoplasms are scarce. We describe the establishment and characteristics of a new MCL cell line, Mino. The cells are large, growing singly and in small clumps in vitro. By flow cytometry, the immunophenotype was compatible with MCL (i.e. CD5+CD20+CD23-FMC7+). Conventional cytogenetics showed hyperdiploidy with multiple complex karyotypic abnormalities, but no evidence of the t(11;14), proven to be present only by fluorescence in situ hybridization and polymerase chain reaction (PCR) methods. Western blots showed expression of cyclin D1 but no detectable cyclin D2 and cyclin D3; the retinoblastoma protein was predominantly phosphorylated. There was expression of tumor suppressor gene products including p53, p16(INK4a), and p21(WAF1). Sequencing of the TP53 gene revealed a mutation (codon 147(valine-->glycine)) in exon 5. Epstein Barr virus was absent. In summary, Mino is a new MCL cell line that may be useful to study the pathogenesis of MCL.
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PMID:Establishment and characterization of a new mantle cell lymphoma cell line, Mino. 1212 61

In March 2000, a 30-year-old Chinese male was initially diagnosed as having non-Hodgkin's lymphoma because of right cervical lymphadenopathy. He had received 8 cycles of chemotherapy including doxorubicin in China. As of February 2001, he was treated in our hospital with the CEPP regimen including etoposide, and was admitted in June 2001 because of leukopenia and thrombocytopenia. Peripheral blood showed hemoglobin 12.7 g/dl, platelets 4.1 x 10(4)/microliter and white blood cells 2300/microliter with 15% blasts. Bone marrow was hypocellular with 48% blasts, which were positive for myeloperoxidase, CD13 and CD33. Chromosome analysis showed 46,XY, t(9;11) (p21;q23) in all 20 metaphase spreads. He was diagnosed as having therapy-related acute myeloblastic leukemia (AML). Because of hypoplastic bone marrow, induction therapy with the CAG regimen including cytarabine, aclarubicin and granulocyte-colony stimulating factor (G-CSF) was started, but no apparent effect was observed. The patient was then treated with the AVG regimen comprising 250 micrograms of G-CSF and continuous infusion with 20 mg of cytarabine and 50 mg of etoposide for 14 days. Complete hematological and cytogenetic remission was achieved after two courses of the AVG regimen. Although it has been shown that the CAG regimen is effective for refractory and/or secondary AML, our results indicate that the AVG regimen should be tried for cases of AML resistant to the CAG regimen.
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PMID:[Successful treatment with G-CSF and continuous infusion of low-dose cytarabine and etoposide for therapy-related acute myeloid leukemia developed during chemotherapy for malignant lymphoma]. 1213 7

A recurrent translocation, t(3;6)(q27;p21), in non-Hodgkin's lymphoma results in fusion of BCL6 with a particular histone H4 gene on 6p21. We cloned five H4/BCL6 junctions from both der(3) and der(6) chromosomes. The breakpoints on H4 were distributed within the single exon or close to the terminal palindrome, and those on BCL6 were localized within or close to the translocation hypercluster. Deletions or duplications of variable numbers of nucleotides were identified at the junctions. A total of eight single nucleotide alterations were introduced into the translocation/mutation cluster of BCL6, whereas four single nucleotide substitutions were identified within a 360-bp region of H4. Thus, the somatic hypermutation mechanism is likely to target H4, resulting in a predisposition to the development of translocation with BCL6. Lymphoma cells carrying H4/BCL6 produced fusion transcripts containing both H4 and BCL6 messages; however, the cells expressed only moderate levels of BCL6 mRNA. We constructed expression plasmids that mimicked the H4/BCL6 fusion gene and transiently introduced them into COS-7 cells. H4/BCL6-transfected cells expressed markedly higher levels of Bcl-6 protein than cells transfected with a plasmid carrying BCL6 driven by its normal promoter and displayed bright nuclear staining with a characteristic punctate pattern with an anti-Bcl-6 antibody. Deletion analyses revealed that the high-level Bcl-6 expression was promoted by the H4 regulatory sequences. The levels of expression of activating transcription factor 3, prefoldin 4, and retinoblastoma-binding protein 7 significantly increased in accordance with that of BCL6, suggesting that Bcl-6 may act as a transcriptional activator. Our study suggested that t(3;6)(q27;p21) leads to BCL6 overexpression; however, the high-level BCL6 expression may not be required to maintain the malignant phenotype of lymphoma cells.
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PMID:Characterization of t(3;6)(q27;p21) breakpoints in B-cell non-Hodgkin's lymphoma and construction of the histone H4/BCL6 fusion gene, leading to altered expression of Bcl-6. 1241 51

Abnormalities in the cell cycle are responsible for the majority of human neoplasias. Most abnormalities occur due to hyperphosphorylation of the tumor suppressor gene Rb by the key regulators of the cell cycle, the cyclin-dependent kinases (CDKs). Thus, a pharmacological CDK inhibitor may be useful in the prevention and/or treatment of human neoplasms. Flavopiridol is a flavonoid with interesting preclinical properties: (1) potent CDK inhibitory activity; (2) it depletes cyclin D1 and vascular endothelial growth factor mRNA by transcriptional and posttranscriptional mechanisms, respectively; (3) it inhibits positive elongation factor B, leading to transcription "halt"; and (4) it induces apoptosis in several preclinical models. The first phase I trial of a CDK inhibitor, flavopiridol, has been completed. Dose-limiting toxicities included secretory diarrhea and proinflammatory syndrome. Antitumor activity was observed in some patients with non-Hodgkin's lymphoma and renal, colon, and prostate cancers. Concentrations between 300 and 500 n M-necessary to inhibit CDK-were achieved safely. Phase II trials with infusional flavopiridol and phase I infusional trials in combination with standard chemotherapy are being completed with encouraging results. A novel phase I trial of 1-h flavopiridol administration was recently completed. The maximum tolerated doses using flavopiridol daily for 5, 3, and 1 consecutive days are 37.5, 50, and 62.5 mg/m(2) per day. Dose-limiting toxicities include vomiting, neutropenia, proinflammatory syndrome, and diarrhea. Plasma flavopiridol concentrations achieved were in the range 1.5-3.5 MICRO M. Phase II/III trials using this 1-h schedule in several tumor types including non-small-cell lung cancer, chronic lymphocytic leukemia, mantle cell lymphoma, and head and neck cancer are being conducted worldwide. UCN-01, the second CDK modulator that has entered clinical trials, has unique preclinical properties: (1) it inhibits protein kinase C (PKC) activity; (2) it promotes cell-cycle arrest by accumulation in p21/p27; (3) it induces apoptosis in several preclinical models; and (4) it abrogates the G(2) checkpoint by inhibition of chk1. The last of these represents a novel strategy to combine UCN-01 with DNA-damaging agents. In the initial UCN-01 clinical trial (continuous infusion for 72 h), a prolonged half-life of about 600 h (100 times longer than in preclinical models) was observed. The maximum tolerated dose was 42.5 mg/m(2) per day for 3 days. Dose-limiting toxicities were nausea/vomiting, hypoxemia, and symptomatic hyperglycemia. One patient with melanoma achieved a partial response (8 months). Another patient with refractory anaplastic large-cell lymphoma had no evidence of disease at >4 years. Bone marrow and tumor samples obtained from some patients revealed loss in adducin phosphorylation, a substrate of PKC. Phase I trials with shorter infusions are being completed. In summary, the first two CDK modulators have shown encouraging results in early clinical trials. A question that remains unanswered is "Which is the best schedule for combination with standard antitumor agents?" Moreover, it is still unclear which pharmacodynamic endpoint reflects loss of CDK activity in tissue samples from patients in these trials. Despite these caveats, we feel that CDKs are sensible targets for cancer therapy and that there are several small-molecule CDK modulators in clinical trials with encouraging results.
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PMID:Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms. 1281 36

Mantle cell lymphoma (MCL) is a distinctive non-Hodgkin's lymphoma subtype, characterized by overexpression of cyclin D1 as a consequence of the chromosomal translocation t(11;14)(q13;q32). MCL remains an incurable disease, combining the unfavourable clinical features of aggressive and indolent lymphomas. The blastic variant of MCL, which is often associated with additional cytogenetic alterations, has an even worse prognosis and new treatment options are clearly needed. The present study investigated the effect of a specific proteasome inhibitor, lactacystin, on cell cycle progression and apoptosis in two lymphoma cell lines harbouring the t(11;14)(q13;q32) and additional cytogenetic alterations, including p53 mutation (NCEB) and p16 deletion (Granta 519). Granta cells were more susceptible to inhibition of the proteasome with respect to inhibition of proliferation and apoptosis induction. No changes were observed in the expression levels of the G1 regulatory molecules cyclin D1 and cdk4, but cell cycle arrest and apoptosis induction was accompanied by accumulation of the cdk inhibitor p21 in both cell lines. Increased p53 expression was only observed in Granta cells with wild-type p53. Cleavage of procaspase-3 and -9 was observed but cleavage of procaspase-8 was not involved in apoptosis induction. The proapoptotic effect of lactacystin was reversed by pretreatment with the pancaspase inhibitor zVAD.fmk. Lactacystin was also effective in inducing apoptosis in lymphoma cells from MCL patients. We conclude that inhibition of the proteasome might be a promising therapeutic approach for this incurable disease.
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PMID:Inhibition of the proteasome induces cell cycle arrest and apoptosis in mantle cell lymphoma cells. 1284 95

We hypothesized that the polymorphisms in the two p53 family genes (p53 Arg72Pro and p73 G4C14-to-A4T14 at exon 2 (G4A)) and p21 Ser31Arg polymorphism might modulate the risk of non-Hodgkin's lymphoma, and conducted a hospital-based prevalent case control study at Aichi Cancer Center Hospital to clarify the association. Risk estimation for each genotype by the unconditional logistic model demonstrated the possible association between the p53 Pro72 allele and the risk of non-Hodgkin's lymphoma in Japanese population (OR = 1.59; 95% CI, 0.99-2.57, P = 0.057), although no other significant association was observed. The analyses of statistical interactions between these three polymorphisms (p73 G4A, p53 Arg72Pro and p21 Ser31Arg polymorphisms) revealed the marginally significant OR for interaction between p53 Arg72Pro and p73 G4A polymorphisms (OR = 2.54; 95% CI, 0.97 6.62, P = 0.057). When those without p53 Pro72 and p73 A4T14 alleles were defined as a reference, those with p53 Pro72 and p73 A4T14 alleles demonstrated a significantly higher OR (2.08; 95% CI, 1.11-3.90, P = 0.023). Further examination with a sufficiently larger population and other ethnicities are required to confirm our findings.
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PMID:Polymorphisms of p53 Arg72Pro, p73 G4C14-to-A4T14 at exon 2 and p21 Ser31Arg and the risk of non-Hodgkin's lymphoma in Japanese. 1529 55


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