Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular pathogenesis of systemic acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHL) is a complex process involving both host factors and the accumulation of genetic lesions within the tumor clone. On the basis of the pattern of molecular lesions involved in these tumors, several distinct pathogenetic pathways can be presently identified in AIDS-related lymphomagenesis. These pathways selectively associate with the different clinicopathologic variants of AIDS-NHL. AIDS-related Burkitt's lymphoma is characterized by activation of c-MYC in all cases, disruption of p53 in 60% of the cases, and infection by Epstein-Barr virus (EBV) in 30% of the cases. AIDS-related diffuse large-cell lymphoma harbor frequent EBV infection (80%) and, in 20% of the cases, BCL-6 rearrangements. Finally, the pathogenesis of AIDS-related body cavity-based lymphoma involves infection by human herpesvirus-8 in all cases and frequently also the co-infection by EBV.
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PMID:Genetic basis of acquired immunodeficiency syndrome-related lymphomagenesis. 970 10

The study of chromosomal changes related to tumor progression in NHL is complicated by the various histologic classification systems and the lack of large serial studies comparing abnormalities at different disease stages. The T-cell lymphomas frequently involve rearrangements of the T-cell receptors and tumor progression is marked by a change from single cell aberrations and polyclonality in low grade disease to monoclonal formation, complex clones, polyploidy, and abnormalities of 1p, 6q, 7, and 13 in high grade T-NHL. In B-cell NHL, specific translocations and oncogene rearrangements are associated with specific NHL subtypes de novo; many of these translocations involve immunoglobulin genes, such as t(14;18) in follicular lymphoma, t(11;14) in MCL, t(3;14) in DLLC, and t(8;14) in Burkitt's lymphoma. Tumor progression is associated with secondary abnormalities which are generally not confined to a particular NHL subtype. Some abnormalities, such as those involving chromosomes 1, 6, and 17, >4-6 clonal markers/cell, and rearrangements of c-MYC and TP53, have prognostic significance while others, such as trisomies 7, 12, 18, and X, are associated with tumor progression but their influence on overall survival is uncertain.
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PMID:Cytogenetic changes in the progression of lymphoma. 972 Jul 11

Mantle cell (centrocytic) non-Hodgkin's lymphoma (MCL) is a malignant tumour with unique biological features. The pathogenesis of MCL seems to be strongly associated with aberrant function of the cell cycle. 110 cases of MCL have been analysed for their cytomorphological features, mitotic and proliferation indices, bcl-1 rearrangements, p53 expression patterns and DNA content by both interphase cytogenetic as well as DNA flow cytometric analyses. According to cytomorphology, three subtypes were recognized: a common, a lymphoblastoid and a pleomorphic variant of MCL. Blastic MCL subtypes were characterized by distinctly elevated mitotic and proliferation indices, frequent bcl-1 rearrangements at the MTC locus, and overexpression of p53. The most interesting finding, however, was a striking tendency of blastoid MCL subtypes to harbour chromosome numbers in the tetraploid range, a feature clearly separating these neoplasms from other types of B-cell NHL and possibly being related to its unphysiological expression of cyclin D1. Although characterised by a uniform immunophenotype and common biological background, MCL shows a broad spectrum of morphological features ranging from small cell to blastic types, and this spectrum is mirrored by distinct biological features.
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PMID:The cytomorphological spectrum of mantle cell lymphoma is reflected by distinct biological features. 1003 1

The p73 gene, a member of the p53 family, is a new candidate tumor suppressor gene. To investigate the possibility of genetic alteration of p73 in leukemia and lymphoma, we examined 55 cell lines and 39 patient samples together with 17 nonhematopoietic cancer cell lines. Gene expression of p73 was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in cell lines (5 of 7 pre B/B-acute lymphoblastic leukemia [ALL], 13 of 21 T-ALL/lymphoblastic lymphomas [LBL], 9 of 10 B-non-Hodgkin's lymphomas [B-NHL], 8 of 9 acute myelogenous leukemias [AML], 2 of 2 T-NHL, 3 of 3 multiple myeloma), and in patient samples (16 of 23 pre B-ALL, 5 of 8 T-ALL/LBL, 5 of 8 B-NHL). PCR-single-strand conformation polymorphism (SSCP) of cDNAs showed no mutation in 43 p73-expressing cell lines within the regions that corresponded to the 5 mutational hotspots of the p53 gene. Neither homologous deletion nor rearrangement of the p73 gene were found by Southern blot analysis in any of the cell lines that lack expression of p73. In contrast to prior published data, analysis of a polymorphic site showed that the p73 gene was expressed biallelically in cell lines and normal peripheral blood. Notably, the p73-negative cell lines were hypermethylated at a CpG island in the 5' untranslated region of the p73 mRNA, and treatment of these cell lines with 5-azacytidine (5-AC), a demethylation reagent, induced p73 expression. Taken together, we found that a sizable proportion (32%) of ALL/B-NHL cell lines and primary tumors had negligible or limited expression of the p73 gene associated with hypermethylation of the gene. These findings suggest that silencing of the p73 gene by hypermethylation may contribute to development and/or progression of lymphoid neoplasms.
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PMID:Loss of p73 gene expression in leukemias/lymphomas due to hypermethylation. 1041 5

Deregulated myc, bcl-2 and/or TP53 gene expression is associated with non-Hodgkin's B cell lymphomas (B-NHLs). Emu-N-myc transgenic mice that misexpress N-myc protein and carry a non-disrupted bcl-2 gene develop indolent B cell lymphomas reminiscent of the B-NHL, follicular lymphoma. Tumors from mice with end-stage disease exhibited discrete, nodular lesions as well as areas of diffuse tumor likely due to coalescence of enlarged follicles. Tumor DNAs were screened for mutations in the Trp53 gene, the murine homologue of the TP53 gene, which participates in B cell differentiation and survival. By PCR-based sequence analyses, we determined there were no mutations in exons 5-8, the common sites of TP53 mutation in B-NHLs. These findings suggested that disease progression in our novel murine lymphoma model may proceed via a Trp53-independent pathogenetic pathway.
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PMID:Mutational analysis of transgenic mouse B cell lymphomas: indication of a Trp53-independent pathway in tumor progression. 1057 40

The genetic mechanisms underlying the genesis, disease progression, and high-grade transformation of marginal zone B-cell lymphoma (MZBCL) are poorly understood. We analyzed 33 cases of histologically and immunophenotypically well-characterized MZBCL (12 extranodal, 11 nodal, and 10 splenic MZBCL; 27 at primary diagnosis and six during the course of disease) by dual-color interphase fluorescence in situ hybridization (FISH) for deletions of tumor suppressor genes. We investigated loci known to play a role in the genesis or disease progression of other subtypes of lymphoid malignancies, namely the P53 gene (17p13), the retinoblastoma gene (RB, 13q14), the D13S25 locus (13q14), and the P16(INK4A) gene (9p21). Heterozygous deletions of P53 were detected in three out of the 33 cases, including two splenic and one extranodal MZBCL. One of these patients was analyzed at primary diagnosis and two during the course of disease. Heterozygous deletions of the RB gene (nodal MZBCL) and D13S25 (splenic MZBCL) were found in one case each. P16 deletions were not detected in any of our cases. We conclude that deletions of the analyzed tumor suppressor genes are relatively rare in MZBCL, which contrasts with the findings in some other subtypes of NHL.
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PMID:Analysis of the P53, RB/D13S25, and P16 tumor suppressor genes in marginal zone B-cell lymphoma: An interphase fluorescence in situ hybridization study. 1091 69

Primary follicular lymphoma of the testis in childhood is extremely rare. To our knowledge, only 5 cases have been reported to date. We report a case in a 6-year-old boy who presented with painless right scrotal enlargement. Right radical orchiectomy revealed a follicular large cell lymphoma with diffuse areas confined to the testis and epididymis, clinical stage IE. Immunohistochemical stains demonstrated that the neoplastic cells were of B-cell lineage, positive for CD10, CD20, CD79a, and BCL-6. Staining for CD21 accentuated networks of dendritic reticulum cells within the nodules. The cells were negative for BCL-2, p53, and T-cell antigens. There was no evidence of the t(14;18) detected by polymerase chain reaction. The data suggest that follicular lymphoma of the testis in children has a different pathogenesis than follicular lymphoma in adults.
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PMID:Primary follicular large cell lymphoma of the testis in a child. 1126 Jun 36

In the highly active antiretroviral therapy (HAART) era, AIDS-related non-Hodgkin's lymphomas (AIDS-NHL) and their treatment still represent an open issue, because HAART may not be sufficient to prevent the development of NHL. The present spectrum of AIDS-NHL includes systemic lymphomas, primary central nervous system lymphomas, and 2 rare entities, primary effusion lymphomas (PEL) and plasmablastic lymphomas of the oral cavity. The vast majority of systemic AIDS-NHL belongs to 3 high-grade B-cell lymphomas: Burkitt's lymphoma (BL), immunoblastic lymphoma (IBL), and large-cell lymphoma (LCL). The pathologic heterogeneity of AIDS-NHL is correlated with the heterogeneity of the molecular lesions associated with these lymphomas. The molecular lesions associated with AIDS-BL involve activation of c-MYC inactivation of p53, and infection by Epstein-Barr virus (EBV). EBV infection occurs in 40% of LCL cases and in 90% of IBL cases. Rearrangements of BCL-6 are detected in 20% of AIDS-LCL cases. In the presence of EBV infection, BCL-6 expressing AIDS-LCL fails to express the latent membrane protein 1 (LMP1) antigen. Conversely, AIDS-IBL are characterized by absent BCL-6 expression, absence of BCL-6 rearrangements, and frequent expression of LMP1. Consistently, the molecular pathways of viral infection and lesions of cancer-related genes associated with AIDS-NHL vary substantially in different clinicopathologic categories of the disease. The marked degree of biologic heterogeneity of AIDS-NHL is highlighted by their histogenetic differences, because AIDS-NHL are related to distinct B cell subsets (ie, germinal center [GC] or post-GC B cells). The phenotypic pattern of AIDS-BL and systemic AIDS-LCL closely reflects B cells residing in the GC, namely centroblasts and centrocytes. Conversely, the phenotype of AIDS-IBL, either systemic or localized primarily to the central nervous system, and AIDS-PEL reflects post-GC B cells in all cases. New information on the molecular and virologic pathogenesis of AIDS-NHL may serve as a point of attack for pathogenic-driven therapies. Moreover, a greater knowledge of other biologic features of these tumors may help investigators identify new potential targets for "intelligent" therapies.
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PMID:AIDS-related non-Hodgkin's lymphomas: from pathology and molecular pathogenesis to treatment. 1205 73

We report the case of a 42-year-old male patient who was diagnosed with a large tumor of the right thoracic aperture 30 months after unrelated hematopoietic stem cell transplantation (HSCT) for accelerated phase of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Biopsy revealed an immature lymphoid neoplasia with blastic tumor cell morphology and immunoreactivity for CD34, CD79a, CD43, and CD30 as well as slight positivity for TdT and CD20. Bcr-Abl rearrangement was found in interphase tumor cell nuclei by fluorescence in situ hybridization (FISH). Furthermore, a translocation t(14;18)(q32;q21) was amplified by polymerase chain reaction (PCR). Bone marrow (BM) examination showed regular hematopoiesis including a negative FISH analysis for Bcr-Abl and complete donor chimerism. Nested PCR from peripheral blood (PB), but not conventional PCR, was positive for the b3a2 Bcr-Abl transcript. Neither radiation nor intensive chemotherapy was capable of achieving a tumor remission, and the patient died from progressive disease 6 months later. Postmortem examinations showed a shift of immunophenotype with appearance of myeloperoxidase-positive tumor cells and loss of lymphoid antigens. In addition, there were characteristic cytogenetic findings of multiple Ph chromosomes and a clonal loss of P53 tumor suppressor gene. The latter was already deleted before HSCT. We conclude that lymphoid neoplasia occurring in our patient should be interpreted as an extramedullary, very immature blast crisis of CML expressing lymphoid differentiation markers rather than a true de novo NHL.
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PMID:Extramedullary blast crisis of chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation mimicking aggressive, translocation t(14;18)-positive B-cell lymphoma. 1257 66

The RB1 pathway and the p53 pathway represent important, interconnected biochemical units frequently perturbed in human cancer. Essential tumor protective mechanisms, such as cellular growth control and apoptosis, are regulated through these systems. Comprehensive studies of these pathways, including most known pathway components, have not been performed in NHL. We therefore analyzed the involvement of aberrations of these pathways in NHLs from the population-based West-Danish NHL registry, LYFO registry, as well as in a series of neurofibromatosis 1-related tumors. The aim of the studies was to obtain information about extent and interrelation of alterations of pathway components, as well as clinical information such alterations might provide. We found that alteration of components of one or both of these pathways are very common, occurring in the vast majority of DLCLs. Our data suggest that the pathways are not entirely linear in lymphomagenesis. The p53 pathway components MDM2 and p53 were frequently altered in the same lymphoma indicating that the role of MDM2 in lymphomagenesis is not entirely dependent on the downstream target, p53. The linearity of the RB1 pathway was clearer as only 1 of 34 DLCLs showed aberration of more than one of the components cyclin D3, p16INK4A, and pRB. An intriguing novel observation was that p16INK4A inactivation was associated with increased expression of cdk4, a kinase target of p16INK4A inhibitory function. This could indicate the existence of a regulatory feedback loop between p16INK4A and cdk4. Cyclin D3 has yet to be established as an oncoprotein. Our finding of cyclin D3 overexpression in a significant number of DLCLs (including all thyroid lymphomas analyzed), as well as the intimate inverse relation to other RB1 pathway alterations suggest, that cyclin D3 is important in lymphomagenesis. However, further studies are needed to implicate cyclin D3 definitively as an oncoprotein. Our data contain several lines of evidence supporting roles of CDKN2A and MDM2 in progression of neoplastic disease. We found that loss of p16INK4A coincided with transformation of neurofibromas to malignant peripheral nerve sheath tumors in neurofibromatosis 1 patients. Furthermore, one DLCL lost CDKN2A from diagnosis to relapse. MDM2 overexpression was more frequent in aggressive than in indolent lymphomas, and in follicle center lymphomas none of our follicle center grade I/II lymphomas overexpressed MDM2. In contrast, MDM2 was overexpressed in 60% of grade III/diffuse follicle center lymphomas. Clinical correlations revealed novel and interesting findings. Both p53 disruption and low expression of E2F-1 correlated with poor response of aggressive lymphomas to treatment. Chemotherapeutic regimens used in lymphoma treatment are based on apoptosis induction, and as both E2F-1 and p53 are regulators of apoptosis, it is possible that the observed treatment failure is associated with reduced E2F-1- and p53-mediated apoptosis. Survival analyses revealed numerous novel and potentially important findings. Several of the studied cell cycle regulators carried independent prognostic value in various subsets of lymphomas. In DLCL, both p16INK4A inactivation and reduced E2F-1 expression conferred shortened survival. p53 alteration was associated with poor prognosis of both B-cell and, especially, T-cell lymphoma. Low expression of p27, a cell cycle regulator haplo-insufficient for tumor suppression, predicted poor outcome in indolent and aggressive lymphoma, and overexpression of cyclin D3 was associated with poor prognosis in indolent lymphomas. Finally, MDM2 overexpression identified among patients with follicle center lymphomas, extranodal marginal zone lymphomas, and mantle cell lymphomas cases with poor prognosis. While these results must necessarily be confirmed on larger prospective series of patients, the data nonetheless suggest that valuable prognostic information can be provided by studies of these cell cycle regulators.
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PMID:Molecular control of the cell cycle in cancer: biological and clinical aspects. 1281 37


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