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)

We present a case of diffuse large B-cell lymphoma CD5 negative, Cyclin D1 positive presenting as ruptured spleen in a 63-year-old man requiring emergent splenectomy. Tumor cells showed marked pleomorphism, anaplasia, and increased mitotic figures with positive Cyclin D1, BCL6, MUM1, P53, and a high MIB1 proliferative fraction. The patient received multiple therapies and ultimately died. This case raises the differential diagnoses of pleomorphic mantle cell lymphoma and other aggressive lymphomas with pleomorphic, anaplastic, and Reed-Sternberg-like cells.
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PMID:CD5 negative, Cyclin D1-positive diffuse large B-cell lymphoma (DLBCL) presenting as ruptured spleen. 1883 19

The BCL6 transcriptional repressor protein has been shown to promote B-cell lymphoma in transgenic mouse models. The mechanism by which BCL6 transforms primary B cells is unclear, although repression of the p53 tumor suppressor is thought to play a role. Here, we showed that BCL6 has critical oncogene functions that are independent of p53 repression. We found that BCL6 cooperates with constitutive CD40 signaling to rapidly transform p53-deficient primary mouse B cells in vitro. Constitutive CD40 signaling alone does not transform p53-deficient B cells, indicating that BCL6 acts specifically as an immortalizing oncogene in this system. The BCL6 transformed B cells are polyclonal and form polyclonal tumors. At the initiation of the cultures, BCL6 does not significantly alter cell cycle progression, but it does promote increased cell survival. Early cultures of BCL6-expressing B cells exhibited marked repression of ATR and p27kip1 but not other BCL6 target genes, suggesting that the ATR and p27kip1 genes have key early roles in mediating BCL6 transformation function. BCL6-transformed cell lines exhibited further decreases of ATR and p27kip1 expression plus strong decreases in Blimp1 and PDCD2 expression. Our study provides important clues about the critical target genes used by BCL6 to transform primary B cells and indicates that the CD40 signaling pathway can collaborate with BCL6 in the transformation of primary B cells. Thus, our study demonstrates a rapid in vitro system to analyze the transformation function of BCL6.
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PMID:BCL6 cooperates with CD40 stimulation and loss of p53 function to rapidly transform primary B cells. 1940 21

Gene copy number and protein expression of topoisomerase IIalpha were correlated to benefit from anthracyclines in various tumors. A retrospective series of 69 patients with DLBCL managed with CHOP chemotherapy were studied for immunohistochemical TopoIIalpha expression and numerical gene abnormalities by fluorescent in situ hybridization (FISH). The results were analyzed in relation to the expression of cell cycle proteins (Ki67, p53, HDM2, p21, p14, pRb, p16, and cyclins A, B1, D1, D2, D3, and E) and BCL6/CD10/MUM1/CD138 B-cell differentiation immunophenotype and outcome. High levels of TopoIIalpha protein were found in 91% of DLBCL cases. No evidence of TopoIIalpha gene amplification or deletion was found. The TopoIIalpha expression showed significant positive correlations with the proliferation index Ki67 (p = 0.002), cell cycle proteins pRb and cyclin D2 (p = 0.018 and p = 0.028, respectively), and the germinal center proteins bcl6 and CD10 (p = 0.010 and p < 0.0001, respectively). TopoIIalpha expression was significantly higher in germinal center B-cell like (GCB) DLBCL than in non-germinal center B-cell like (non-GCB) DLBCL (p = 0.048). TopoIIalpha protein was significantly associated with response to chemotherapy (chi(2), p = 0.024), but not with relapse-free or overall survival (p = 0.5). On multivariate analysis, only stage of disease retained independent prognostic significance (HR 0.33 for early stage, p = 0.008). Although TopoIIa gene copy number abnormalities were not found in DLBCL, high levels of protein expression are associated with GCB-cell differentiation immunophenotype, high proliferation, and response to treatment.
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PMID:High levels of topoisomerase IIalpha protein expression in diffuse large B-cell lymphoma are associated with high proliferation, germinal center immunophenotype, and response to treatment. 2049 3

BCL6 protects germinal center (GC) B cells against DNA damage-induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7-dependent B cell precursors, we report that IL-7Ralpha-Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a mu heavy chain, however, activation of pre-B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Ralpha-Stat5 signaling is attenuated. At the transition from IL-7-dependent to -independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre-B cells from DNA damage-induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre-B cell self-renewal and the formation of a diverse polyclonal B cell repertoire.
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PMID:BCL6 is critical for the development of a diverse primary B cell repertoire. 2049 19

In this study, we reviewed epigenetic therapy of lymphomas using histone deacetylase inhibitors (HDACi), a promising new class of antineoplastic agents. Epigenetic therapy, a new therapeutic concept, consists of the use of HDACi and or DNA methyltransferase inhibitors (DNMTi). We conducted a comprehensive review of the literature for antitumour activity of HDACi and its mechanism of action. HDACi modify the expression of several genes related to cancer development, which can result in antineoplastic activity. To elucidate the benefits of HDACi in lymphoma treatment, we discuss the crucial interplay between BCL6, p53 and STAT3. Activated B-cell (ABC) diffuse large cell lymphoma (DLCL) is increasingly being recognised as an unfavourable and frequently therapy-refractory lymphoma. We discuss the fundamental causative role of the STAT3 oncogene in ABC type DLCL. STAT3 can be effectively suppressed by several HDACi, a promising treatment for this difficult subtype of DLCL. On the other hand, various HDACi can repress the germinal-centre B Cell (GCB) type DLCL by virtue of their inhibition of the BCL6 oncogene, usually expressed in this particular subtype. We summarise the results of recent clinical trials with HDACi such as romidepsin, panobinostat, MGCD-0103, entinostat, curcumin, JAK2 inhibitor TG101348, and valproic acid that have shown preliminary activity in recurrent and refractory lymphomas. The unique mechanism of action of HDACi makes them very attractive agents to pursue in combination. Several ongoing trials are already exploring HDACi combinations in various types of cancers. Their role in front-line management remains to be determined.
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PMID:Epigenetic therapy of lymphoma using histone deacetylase inhibitors. 2053 95

Precursor B lymphoblastic neoplasm usually presented as childhood leukemia. Most precursor lymphoblastic lymphoma are T-cell lineage and precursor B lymphoblastic lymphoma constitutes only about 10% of cases according to the WHO Classification of Tumours of Haematologic and Lymphoid Tissues. The most frequent sites of involvement in precursor B lymphoblastic lymphoma are the skin, soft tissue, bone and lymph nodes. Primary appendiceal involvement is an uncommon condition. We present an unusual case of primary appendiceal precursor B lymphoblastic lymphoma in an 11-year-old boy with peculiar histological morphology mimicking diffuse large B cell lymphoma. Histologically, the tumor was composed of diffusely infiltrated large cells from mucosa and extended to the subserosal area. The tumor cells were positive to CD79a, CD20, PAX5, BCL2, CD10, TdT, p53 but not to CD3, BCL6 and CD34 by immunohistochemical studies. The response to conventional treatment regimen for lymphoblastic lymphoma was not good, with early relapse within three months. Partial remission was achieved by adding rituximab. Unfortunately, the patient died in ten months due to uncontrolled relapsed disease with generalized lymphadenopathy and massive pleural effusion. The special morphologic changes and poor response to chemotherapy may be related to the overexpression of p53.
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PMID:Primary appendiceal precursor B lymphoblastic lymphoma with peculiar morphology mimicking diffuse large B cell lymphoma. 2084 68

Recently, it has been reported that, in several tumor cell lines, short double-stranded RNAs tailored for promoter regions of specific genes are able to activate their transcription. Such molecules (named RNA activators) act opposite to other double-stranded RNA molecules (named RNA inhibitors) in that the overexpression instead of underexpression of a given gene is triggered. In Dohh2 non-Hodgkin lymphoma cells, the transcriptional repressor BCL6, which negatively controls both p53 and p21, is overexpressed, so that the cells can escape the check point governed by p53 and proliferate. The aim of this work was to investigate whether the RNA activator p21 can represent a tool to circumvent the transcriptional control of BCL6 and induce the blockage of cell proliferation in Dohh2 non-Hodgkin lymphoma cells. For that, Dohh2 cells were transfected with either a control RNA activator (ds-NC) or an RNA activator specific for human p21 promoter (ds-p21). At various time points after transfection, the cells were collected and p21 was measured. Dohh2 cells transfected with ds-p21 showed a slight but significant overexpression of p21 at both mRNA and protein levels. Nonetheless, cell proliferation, cell cycle, and apoptosis were not significantly modified. In contrast, the exposure of Dohh2 cells transfected with ds-p21 to fludarabine potentiates the cytotoxicity of the drug, suggesting the RNA activator p21 complements the fludarabine-dependent cell death pathways.
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PMID:The RNA activator ds-p21 potentiates the cytotoxicity induced by fludarabine in Dohh2 cells. 2124 Nov 87

B-cell non-Hodgkin's lymphoma comprises biologically and clinically distinct diseases the pathogenesis of which is associated with genetic lesions affecting oncogenes and tumour-suppressor genes. We report here that the two most common types--follicular lymphoma and diffuse large B-cell lymphoma--harbour frequent structural alterations inactivating CREBBP and, more rarely, EP300, two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signalling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these two genes. These lesions usually affect one allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. We demonstrate specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein and activation of the p53 tumour suppressor. These results identify CREBBP/EP300 mutations as a major pathogenetic mechanism shared by common forms of B-cell non-Hodgkin's lymphoma, with direct implications for the use of drugs targeting acetylation/deacetylation mechanisms.
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PMID:Inactivating mutations of acetyltransferase genes in B-cell lymphoma. 2139 Jan 26

The primary function of B cells, critical components of the adaptive immune response, is to produce antibodies against foreign antigens, as well as to perform isotype class switching, which changes the heavy chain of an antibody so that it can interact with different repertoires of effector cells. CD40 is a member of the tumor necrosis factor superfamily of cell surface receptors that transmits survival signals to B cells. In contrast, in B cell cancers, stimulation of CD40 signaling results in a heterogeneous response in which cells can sometimes undergo cell death in response to treatment, depending on the system studied. We found an association between sensitivity to CD40 stimulation and mutation of the tumor suppressor p53 in a panel of non-Hodgkin's lymphoma cell lines. Consistent with p53's tumor suppressor role, we found that higher levels of intrinsic DNA damage and increased proliferation rates, as well as higher levels of BCL6, a transcriptional repressor proto-oncogene, were associated with sensitivity to CD40 stimulation. In addition, CD40 treatment-resistant cell lines were sensitized to CD40 stimulation after the introduction of DNA-damaging agents. Using gene expression analysis, we also showed that resistant cell lines exhibited a preexisting activated CD40 pathway and that an mRNA expression signature comprising CD40 target genes predicted sensitivity and resistance to CD40-activating agents in cell lines and mouse xenograft models. Finally, the gene signature predicted tumor shrinkage and progression-free survival in patients with diffuse large B cell lymphoma treated with dacetuzumab, a monoclonal antibody with partial CD40 agonist activity. These data show that CD40 pathway activation status may be useful in predicting the antitumor activity of CD40-stimulating therapeutic drugs.
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PMID:CD40 pathway activation status predicts response to CD40 therapy in diffuse large B cell lymphoma. 2141 38

Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication of solid organ transplantation or, more rarely, hematopoietic stem cell transplantation. The majority of PTLD is of B-cell origin and associated with Epstein-Barr virus (EBV) infection. PTLD generally display involvement of extranodal sites, aggressive histology and aggressive clinical behavior. The molecular pathogenesis of PTLD involves infection by oncogenic viruses, namely EBV, as well as genetic or epigenetic alterations of several cellular genes. At variance with lymphoma arising in immunocompetent hosts, whose genome is relatively stable, a fraction of PTLD are characterized by microsatellite instability as a consequence of defects in the DNA mismatch repair mechanism. Apart from microsatellite instability, molecular alterations of cellular genes recognized in PTLD include alterations of cMYC, BCL6, TP53, DNA hypermethylation, and aberrant somatic hypermutation of protooncogenes. The occurrence of IGV mutations in the overwhelming majority of PTLD documents that malignant transformation targets germinal centre (GC) B-cells and their descendants both in EBV-positive and EBV-negative cases. Analysis of phenotypic markers of B-cell histogenesis, namely BCL6, MUM1 and CD138, allows further distinction of PTLD histogenetic categories. PTLD expressing the BCL6+/MUM1+/-/CD138- profile reflect B-cells actively experiencing the GC reaction, and comprise diffuse large B-cell lymphoma (DLBCL) centroblastic and Burkitt lymphoma. PTLD expressing the BCL6-/MUM1+/CD138- phenotype putatively derive from B-cells that have concluded the GC reaction, and comprise the majority of polymorphic PTLD and a fraction of DLBCL immunoblastic. A third group of PTLD is reminiscent of post-GC and preterminally differentiated B-cells that show the BCL6-/MUM1+/CD138+ phenotype, and are morphologically represented by either polymorphic PTLD or DLBCL immunoblastic.
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PMID:Post-transplant lymphoproliferative disorders: role of viral infection, genetic lesions and antigen stimulation in the pathogenesis of the disease. 2141 4


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