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)

Diffuse large B cell lymphomas (DLBLs) represent a heterogeneous collection of aggressive non-Hodgkin's lymphomas that can arise either de novo or as a result of transformation from chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphomas, or lymphomas of mucosa-associated lymphoid tissue. A small percentage of DLBLs express the CD5 antigen. The majority of these cases have evolved from a pre-existing low grade non-Hodgkin's lymphoma (Richter's syndrome). However, we identified and characterized nine CD5-positive DLBLs in which the patients did not have a previous history or concomitant evidence of chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, or mucosa-associated lymphoid tissue-associated non-Hodgkin's lymphoma, suggesting that they arose de novo. All nine cases expressed CD20 and monotypic immunoglobulin, all eight cases examined expressed CD19, CD22 and CD43, eight of the nine cases expressed HLA-DR, and two of eight cases expressed CD11c. None of the cases expressed CD3, CD10, CD11b, CD21, CD23 or CD30. CD5 expression by these cells was found to be identical to that of CD5-positive B cell chronic lymphocytic leukemia by quantitative polymerase chain reaction analysis of CD5 mRNA. These nine de novo CD5-positive DLBLs exhibited clonal immunoglobulin heavy and light chain gene rearrangements but lacked integration of the Epstein-Barr virus genome and structural alterations of the bcl-1, bcl-2, c-myc, H-ras, K-ras, and N-ras proto-oncogenes and the p53 tumor suppressor gene. However, bcl-6 proto-oncogene rearrangement, which is involved in chromosome band 3q27 aberrations, was found in four cases (44.4%). This is comparable with the frequency of bcl-6 gene rearrangement in CD5-negative DLBL. In contrast, bcl-6 gene rearrangement was absent in six cases of DLBL associated with Richter's syndrome. These findings suggest that de novo CD5-positive DLBLs are genotypically similar to CD5-negative DLBLs and may be pathogenetically distinct from the DLBLs associated with Richter's syndrome.
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PMID:De novo CD5-positive and Richter's syndrome-associated diffuse large B cell lymphomas are genotypically distinct. 754 11

Two new myeloid cell lines (K051 and K052) were established from a patient with multilineage CD7-positive acute leukemia. The K051 and K052 were established from the patient's bone marrow cells at diagnosis and at relapse, respectively. The K051 cell expressed myeloid-associated antigens (CD13 and CD33), a platelet-associated antigen (CD41), and an erythroid antigen (glycophorin A). The K052 cell expressed myeloid-associated antigens (CD13, CD14, and CD33), lymphoid markers (CD2, CD5, and CD7), and HLA-DR. Chromosome analysis of both cell lines showed a 17p- chromosome. Both cell lines were investigated for aberrations of the p53 gene and the N-ras gene. A p53 mutation detected in both cell lines consisted of a C-->T substitution in codon 248. An N-ras mutation detected only in the K052 cell consisted of a G-->C substitution in codon 13. Expression of the multidrug resistance gene (MDR1) was also investigated by the semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). MDR1-mRNA was more highly expressed by the K052 cell than the K051 cell, being equivalent to that in HEL cells. The functional MDR1-protein against vincristine was also observed, and its function was inhibited by verapamile and Cyclosporin A. The K052 cells were capable of phenotypic or morphologic differentiation after being incubated with granulocyte colony-stimulating factor, interleukin-2, phorbol 12-myristate 13-acetate, or 1,25-dihydroxy-vitamin D3. In contrast, the K051 cells responded phenotypically to retinoic acid. Thus, the K051 and K052 cell lines will be useful for investigating the cellular and molecular events in leukemogenesis and differentiation, and the mechanism of expression of the MDR1 gene.
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PMID:p53 and N-ras mutations in two new leukemia cell lines established from a patient with multilineage CD7-positive acute leukemia. 769 50

A phenotypic and molecular evaluation was made of 15 patients with mature B-cell leukemia/lymphoma showing exclusive spleen and bone marrow involvement. According to French-American-British criteria, these cases could not be classified as classical B-cell chronic lymphocytic leukemia, hairy cell leukemia and its variant forms, splenic lymphoma with villous lymphocytes, or leukemic phase non-Hodgkin's lymphoma (NHL; follicular or intermediate type). The immunophenotype pattern (high surface Ig and CD25 expression, and little or no reactivity with CD5, CD23, and CD11c) and cytomorphologic features of these neoplasms suggested an origin in the marginal zone of the spleen. Molecular analysis did not show any involvement of the dominantly acting oncogenes generally associated with lymphoid malignancies (c-myc, bcl-2, bcl-1, Ras), but mutations of the p53 tumor suppressor gene involving exons 5, 6, and 8 were found in 6 cases (6 of 15, 40%). In 4 cases, the p53 alterations consisted of a point mutation leading to amino acid substitution. In the remaining 2 cases, an insertion or deletion resulting in a frame-shift of the protein was observed. In all but 1 of the cases, the wild-type sequence at the mutation site was barely visible, implying the loss of the normal p53 allele in leukemic cells. All of the cases showed a clinical course compatible with that of low-grade NHL, regardless of the p53 loss/mutation. Overall, our data suggest the existence of a form of splenic B-cell leukemia/lymphoma of possible marginal zone origin in which p53 inactivation may play an important pathogenetic role.
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PMID:Frequent p53 gene involvement in splenic B-cell leukemia/lymphomas of possible marginal zone origin. 801 22

B cell chronic lymphocytic leukemia (B-CLL) represents the most frequent adult leukemia in the Western world. The molecular pathogenesis of B-CLL is largely unknown. Although initial reports on small panels of cases had suggested a role for Bcl-1 and Bcl-2 oncogene activation in B-CLL, later investigations failed to confirm these data. Among tumor suppressor genes, p53 mutations have been reported in a fraction of cases. In this study, we have attempted a conclusive definition of the involvement of dominantly acting oncogenes (Bcl-1 and Bcl-2) and tumor suppressor loci (p53, 6q-) in 100 cases of B-CLL selected for their CD5 positivity and Rai's stage (0 to IV). Rearrangements of Bcl-1 and Bcl-2 and deletions of 6q and 17p were analyzed by Southern blot using multiple probes. Mutational analysis (single strand conformation polymorphism and polymerase chain reaction direct sequencing) was used to assay p53 inactivation. No alterations of Bcl-1 or Bcl-2 were detected in the 100 cases tested. Mutations of p53 were found in 10/100 cases without any significant association with clinical stage. Deletions of 6q were present in 4/100 cases. Overall, our data indicate that: 1) contrary to previous reports, Bcl-1 and Bcl-2 rearrangements are not involved in CD5+ B-CLL pathogenesis and 2) p53 mutations are present in 10% of cases at all stages of the disease.
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PMID:Analysis of alterations of oncogenes and tumor suppressor genes in chronic lymphocytic leukemia. 820 69

Splenic marginal zone cell lymphoma (SMZCL) is a recently described clinicopathologic entity, that is reported to overlap with splenic B-cell lymphoma with villous lymphocytes. The authors describe the clinicopathologic, immunophenotypic, and molecular findings in five cases of SMZCL. There were two males and three females, with a mean age of 68.4 years, who presented with peripheral blood cytopenias and splenomegaly. One patient had an absolute lymphocytosis with many villous lymphocytes. With clinical follow-up of 9 to 37 months, two patients are alive and three patients died of unrelated causes. Splenectomy was done in each patient and the spleens were large, 970-2,400 g. Histologically, the SMZCLs preferentially replaced the marginal and mantle zones with partial or complete replacement of germinal centers in the white pump. The neoplastic cells were predominantly small to medium in size with oval or slightly irregular nuclei and relatively abundant pale or eosinophilic cytoplasm. Immunophenotypic studies demonstrated that the neoplastic cells expressed monotypic immunoglobulin, IgD in four tumors, pan-B-cell antigens, and bcl-2. The tumor cells were negative for the CD2, CD3, CD5, CD10, CD11c, CD25, CD35, CD38, CD45RO, and CD68 antigens, and tartrate-resistant acid phosphatase. Southern blot hybridization revealed immunoglobulin gene rearrangements in all tumors. The major breakpoint region of the bcl-2 gene and the T-cell receptor beta chain gene were in the germline configuration. Polymerase chain reaction studies did not identify the t(14;18) or t(11;14). All cases were negative for p53 protein and single-stranded conformational polymorphism analysis for p53 gene mutations was negative. Our results support the concept that SMZCL is a clinically indolent, low grade B-cell lymphoma that probably arises from splenic marginal zone lymphocytes.
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PMID:Splenic marginal zone cell lymphoma. An immunophenotypic and molecular study of five cases. 860 7

An unusual case of low-grade B-cell lymphoproliferative disorder with peripheral lymphocytosis and splenomegaly followed for 4 1/2 years is reported. During this period, the phenotype of the tumor cells in the blood changed from that of hairy cell leukemia (HCL)/chronic lymphocyte leukemia (CLL) to HCL/prolymphocytic leukemia (PLL), to PLL. The lymphoid population in the blood showed a mixture of hairy cells, villous lymphocytes, small lymphocytes, and prolymphocytes, corresponding to the phenotypes at various stages. Although relatively specific markers for CLL, HCL, and PLL, such as CD5, CD11c, CD22, CD25, and FMC-7, were positive at various stages, all these markers have also been demonstrated in a large study series of splenic lymphoma with villous lymphocytes (SLVL). In addition, the histologic pattern of the bone marrow biopsy and splenectomy specimen were not typical for HCL. This case can therefore be classified either as HCL variant or as SLVL. As SLVL assumes various cytologic and histologic patterns, which overlap with different lymphoproliferative disorders, especially HCL variants, this entity appears to represent a heterogeneous group of lymphomas/leukemias that may evolve into each other. The absence of activation of c-myc and bc1-2 oncogenes as well as mutation of p53 tumor suppressor gene, together with the presence of only one single rearranged band for both heavy chain and kappa light chain genes in our case suggest that these morphologically different lymphoid tumors may belong to the same family.
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PMID:Relationship between hairy cell leukemia variant and splenic lymphoma with villous lymphocytes: presentation of a new concept. 860 28

Large-cell variants are uncommon in mantle cell lymphoma (MCL). Here we describe the pathologic and clinical findings in five patients with large-cell lymphoma related to MCL (L-MCL), and compare them to a group of classic small-cell MCL (s-MCL) cases. Histologically, the MC origin of the large cells was evinced by their association with a small mantle cell component in the same tissue, or their distribution in a classic mantle zone pattern, or their development in a patient with previous s-MCL. The large cells were either pleomorphic mantle cells (case 1) or transformed blast-like cells (case 2-5). The median nuclear diameter, median nuclear area and proliferation index of L-MCLs and s-MCLs, were statistically different. Immunophenotypic characterization of four specimens of L-MCL and 10 of s-MCLs with a large panel of antibodies showed the classic findings of MCL, i.e. the IgM+ D+/-, CD5+, CD10-, CD23- phenotype in all cases except two (one CD5- and one CD23+), and the association with a loose follicular dendritic cell network. Two of four L-MCLs and 5/10 s-MCLs demonstrated rearrangements of the bcl-1 gene by Southern blot or by polymerase chain reaction (PCR); 2/4 L-MCLs and 1/9 s-MCLs had p53 mutations on single-strand conformation polymorphism analysis; none of the 14 specimens showed rearrangement of bcl-2 by PCR or bcl-6 and c-myc by Southern blot. All patients with 'transformed' histology (versus 37% of all others) died of lymphoma; their survival (15-18 months; median 17) was much shorter than that of all the others (28-117+ months; median 43) (P=0.0035). All three patients with p53 anomalies, two of whom had tumours with transformed histology, died of their disease in a short time (15, 18 and 28 months). In contrast, the presence of bcl-1 rearrangements did not have prognostic implications. This study documents the existence of large-cell variants of MCL and the poor prognosis associated with the 'transformed' cytologic type and/or p53 abnormalities.
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PMID:Large-cell variants of mantle cell lymphoma: cytologic characteristics and p53 anomalies may predict poor outcome. 863 52

The immunoglobulin (Ig) variable region (V) genes expressed by IgM chronic lymphocytic leukemia (CLL) B cells display little or no somatic mutations. However, preliminary findings have shown that Ig V genes of IgA and IgG CLLs may be somatically mutated, suggesting that isotype-switched CLLs may represent a "subtype" of the disease. To investigate the degree and nature of somatic mutations and the role of antigen (Ag) in the clonal selection and expansion of isotype-switched CLLs, and to determine whether specific oncogene or tumor suppressor gene mutations are associated with isotype-switched CLLs, we analyzed the expressed Ig VH gene, bcl-1 and bcl-2 proto-oncogene, and p53 tumor suppressor gene configurations of 3 IgA-, 1 IgG-, and 1 IgA/ IgG-expressing CLLs. These isotype-switched CLL B cells expressed surface HLA-DR, CD19, CD23, and CD5, and displayed no alterations of the bcl-1 and bcl-2 oncogenes and the p53 tumor-suppressor gene. The cDNA VH-D-JH gene sequence was joined with that of the C alpha gene in the B cells of the three IgA CLLs, and with that of the C gamma gene in the IgG CLL B cells. In the IgA/IgG-coexpressing CLL B cells, identical VH-D-JH cDNA sequences were spliced to either C alpha or C gamma genes. In all five CLLs, the pattern of C mu DNA probe hybridization to the digested genomic DNAs was consistent with deletion of the C mu exon from the rearranged Ig gene locus, suggesting that these CLL B cells had undergone DNA switch recombination. In one IgA CLL, the expressed VH gene was unmutated. In all other class-switched CLLs, the Ig VH segment gene was mutated, but the point mutations were not associated with intraclonal diversification. In one IgA and in the IgA/IgG-coexpressing CLL, the nature and distribution of the mutations were consistent with Ag selection. These findings suggest that IgA- and/or IgG-expressing CLLs represent, in their VH gene structure, transformants of B cells at different stages of ontogeny. They also suggest that Ag may play a role in the clonal selection of some of these isotype-switched leukemic cells, but bcl-1 and bcl-2 oncogene rearrangements and p53 tumor suppressor gene mutation are not associated with the pathogenesis of isotype-switched CLLs.
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PMID:Molecular characterization of IgA- and/or IgG-switched chronic lymphocytic leukemia B cells. 905 57

Thymic carcinoma is an uncommon tumor. Most cases appear to arise de novo, but in rare instances they can arise in thymomas. We report the clinicopathologic features and immunohistochemical profile of five cases of thymic carcinoma accompanied by a component of thymoma. Immunohistochemical studies were performed with the avidin-biotin-peroxidase complex method using monoclonal antibodies to p53(DO7), CD99(O13), epithelial membrane antigen, CD5(NCL-CD5-4C7), vimentin (V9), and cytokeratins 7, 8, 18, and 19. The patients consisted of three men and two women with a median age of 57 years. One patient had myasthenia gravis, and the other four presented with chest symptoms. One patient had concurrent adenocarcinoma of the lung with metastasis. Four of the patients died within 15 months. The thymomas consisted of two large polygonal cell thymomas, two squamoid thymomas, and one spindle cell thymoma. The malignant components included two undifferentiated carcinomas, one spindle cell carcinoma, one squamous cell carcinoma, and one clear cell carcinoma with squamous differentiation. There was no correlation between the histologic types of the thymoma and the thymic carcinoma. In three cases, excluding the two squamoid thymomas, the thymic carcinomas occurred in the necrotic areas of the thymoma. They showed upregulated expression of epithelial membrane antigen and cytokeratins 7, 8, 18, and 19, similar to the so-called "interface phenomenon" described in the invasion front of other types of carcinoma. Increased p53 protein expression was observed in all five carcinomas, and there was loss of CD99+ immature T lymphocytes. Among the thymic carcinomas, only the squamous component of the clear-cell carcinoma stained for CD5, a marker commonly expressed in thymic carcinomas. Paradoxically, a squamoid thymoma, but not its associated spindle cell carcinoma, expressed CD5, suggesting the acquisition of an "aggressive" phenotype by the squamoid thymoma, but with loss of the marker on malignant transformation. One undifferentiated carcinoma acquired vimentin immunoreactivity, whereas four other carcinomas and all five thymomas were negative. In conclusion, thymic carcinoma can arise in any histologic type of thymoma, including spindle cell thymoma, which is generally regarded as a benign neoplasm. The prognosis appears to be poor. Tumor necrosis in a thymoma should alert the pathologist to search for malignant change. The malignant change is commonly associated with increased expression of epithelial membrane antigen, cytokeratin subtypes, or p53 protein, and loss of CD99+ immature T lymphocytes, and is occasionally associated with a change in the expression of CD5 or vimentin.
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PMID:Thymic carcinoma arising in thymoma is associated with alterations in immunohistochemical profile. 985 Jan 73

The molecular pathology and histogenesis of lymphomas in 56 retired breeder male and 14 12-week-old male homozygous p53-deficient (p53-/-) mice (C57BL/6TacfBR-[KO]p53 N4) were evaluated. Lymphomas were assessed by serial morphologic techniques, immunohistochemistry, flow cytometry, and analysis of T cell receptor (TCR) or immunoglobulin heavy chain (IgH) gene rearrangements. We found two common types of lymphomas. T-cell lymphomas arose in the thymus through a sequence of lymphocyte depletion, medullary hyperplasia, and unilateral lymphoma. Tumor cells were CD3+, CD90+, and usually TCRalpha/beta+ and possessed clonal TCRbeta gene rearrangements. Thymic lymphoblastic lymphomas (LL) were highly malignant and quickly metastasized to the splenic white pulp and liver, even when the thymus was only slightly increased in weight. In the spleen, a novel lymphoma was found. Marginal zone hyperplasia led to marginal zone lymphoma (MZL), a well-differentiated lymphoma that usually expressed CD45R (B220) and CD5 at low levels and that had clonal IgH gene rearrangements. IgH gene rearrangements were also seen in spleens with marginal zone hyperplasias only. Hyperplastic and neoplastic marginal zone B cells expressed IgM at low to normal levels, as seen by FACS analysis and immunohistochemistry. These tumors only metastasized to the liver at a later stage, as they became less differentiated. Several mice had both types of tumors present in the spleen. Two B-cell lymphoblastic lymphomas of uncertain origin were also found. In this article, we discuss the possible mechanisms responsible for development of the lymphomas seen in these p53-deficient mice.
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PMID:Splenic marginal zone B-cell and thymic T-cell lymphomas in p53-deficient mice. 995 6


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