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 have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direct sequencing of PCR-amplified fragments. Mutations were found associated with (i) Burkitt lymphoma (9/27 biopsies; 17/27 cell lines) and its leukemic counterpart L3-type B-cell acute lymphoblastic leukemia (5/9), both of which also carry activated c-myc oncogenes, and (ii) B-cell chronic lymphocytic leukemia (6/40) and, in particular, its stage of progression known as Richter's transformation (3/7). Mutations were not found at any significant frequency in other types of non-Hodgkin lymphoma or acute lymphoblastic leukemia. In many cases, only the mutated allele was detectable, implying loss of the normal allele. These results suggest that (i) significant differences in the frequency of p53 mutations are present among subtypes of neoplasms derived from the same tissue; (ii) p53 may play a role in tumor progression in B-cell chronic lymphocytic leukemia; (iii) the presence of both p53 loss/inactivation and c-myc oncogene activation may be important in the pathogenesis of Burkitt lymphoma and its leukemic form L3-type B-cell acute lymphoblastic leukemia.
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PMID:p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. 205 20

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

p53 protein expression has been investigated by immunohistochemistry in 58 patients with leukemia. Seven of 24 cases with acute myeloid leukemia (AML), 3 of 15 cases with chronic lymphocytic leukemia (CLL), one of 11 cases with chronic myeloid leukemia (CML) and 4 of 8 cases with acute lymphoid leukemia (ALL) had p53 protein expression. Of patients having p53 expression, one case with AML had refractory anemia with excess blasts-transformation (RAEB/t), one case with CLL had Richter's syndrome and another one with CML was in accelerated phase. Finally, 26% of leukemia cases had p53 protein expression. It may be concluded that p53 protein abnormalities may have an important role in leukomogenesis and in the development of more malignant clones in chronic leukemias.
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PMID:p53 protein expression in leukemias. 786 30

Paired samples of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and the subsequent diffuse large cell lymphoma (DLL) of six cases of Richter's syndrome were investigated to establish the clonal relationship between the CLL/SLL and the DLL components and to define the oncogene and/or tumor-suppressor gene alterations involved in the morphologic transformation of CLL/SLL. Southern blot hybridization analysis showed identical clonal immunoglobulin (Ig) gene-rearrangement patterns in the CLL/SLL and DLL components in four cases and different Ig gene-rearrangement patterns in two cases. Polymerase chain reaction (PCR) amplification, cloning, and DNA sequencing of complementary determinant region 3 (CDR3) of the Ig-heavy chain gene of one of the two cases in which the Ig gene-rearrangement patterns were different showed nonidentical sequences in the CLL/SLL and DLL components. In the other case, monomorphic Epstein-Barr virus (EBV) genome integration was detected in the DLL but not in the CLL, suggesting that the CLL and DLL components in this case of Richter's syndrome also represent unrelated clones. Single-strand conformation polymorphism (SSCP) analysis and sequencing of exons 5 through 9 of the p53 tumor-suppressor gene showed a mutation in codon 176 of the DLL but not in the CLL/SLL component in one case where the CLL/SLL and DLL represented different clones. The p53 mutation probably played a role in the development of the lymphoma rather than morphologic transformation of the CLL/SLL in this case. SSCP analysis and sequencing also showed identical mutations in codon 282 in both the CLL/SLL and DLL components in a case where the CLL and DLL represented identical clones. Thus, this p53 gene mutation was present both before and after morphologic transformation, and therefore, probably did not play a primary role in this process. Southern blot hybridization analysis failed to show evidence of bcl-1, bcl-2, c-myc proto-oncogene or retinoblastoma (Rb) tumor-suppressor gene rearrangements in these six cases of Richter's syndrome. In conclusion, the original CLL/SLL and the subsequent DLL in Richter's syndrome may or may not be derived from identical clones, and the well-known proto-oncogenes and tumor-suppressor genes do not appear to play an obvious and consistent role in the morphologic transformation of CLL/SLL to DLL.
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PMID:Molecular genetic demonstration of the diverse evolution of Richter's syndrome (chronic lymphocytic leukemia and subsequent large cell lymphoma). 811 38

Clinicobiological, histological, cytogenetic and molecular genetic studies were performed in a case of atypical B-cell chronic lymphocytic leukaemia (B-CLL) with the t(11;14)(q13;q32) evolving into Richter's syndrome (RS) in order (a) to determine the clonal relationship between the cell of origin for B-CLL and RS, and (b) to analyse genetic events underlying the disease progression in this patient. After 4 years following diagnosis, a rapid deterioration of the clinical picture occurred, concomitant with the appearance of large lymphoid blasts in peripheral blood (PB), bone marrow (BM) and ascites samples. A diagnosis of RS was made and cytogenetic analysis revealed karyotype evolution with trisomy 7 and del(17p) in addition to t(11;14). Fluorescence in situ hybridization showed 78% lymphoid blast cells obtained from ascites sample to be trisomic using a chromosome-7-specific pericentromeric probe. Whereas no rearrangement of the c-myc proto-oncogene was detected at disease progression, direct sequencing of p53 gene exon 5-9 revealed an exon 7 missense point mutation. This abnormality was not present in the CLL phase. Immunological staining with the monoclonal antibody PAb-1801, detecting the p53 protein product, revealed a negative pattern in the CLL phase, whereas 24% positivity was documented in representative samples obtained at RS. It is concluded that RS was cytogenetically related with B-CLL in this patient, suggesting the occurrence of a bona fide transformation and that the mutation of p53 exon 7, in association with the development of 17p deletion, possibly played a role in the development of RS.
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PMID:Richter's syndrome in a case of atypical chronic lymphocytic leukaemia with the t(11;14)(q13;q32): role for a p53 exon 7 gene mutation. 860 3

Low grade B-cell non-Hodgkin's lymphomas (B-NHL) represent a markedly heterogeneous group of lymphoproliferative disorders, including B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CCL/SLL), lymphoplasmacytoid lymphoma (LPL), follicular lymphoma (FL), mucosa-associated lymphoid tissue lymphoma (MALTL), and splenic lymphoma with villous lymphocytes (SLVL). The molecular pathogenesis of low grade B-NHL is characterized by distinct genetic pathways which selectively associate with each clinicopathologic category. At diagnosis, B-CLL/SLL frequently display deletions of 13q14 and trisomy 12, whereas evolution to Richter's syndrome associates with disruption of p53. LPL carries t(9;14)(p13;q32) in 40-50% of the cases, leading to the deregulated expression of the PAX-5 gene. FL consistently harbors rearrangements of BCL-2 independent of the cytologic variant. With time, a fraction of FL cases accumulates mutations of p53 and evolves into a high grade B-NHL. Low grade MALTL are characterized by the frequent occurrence of trisomy 3 and, occasionally, by p53 mutations. SLVL carries p53 mutations in a fraction of cases. The identification of distinct genetic categories among low grade B-NHL may help in the therapeutic stratification of these disorders. In addition, genetic lesions of low grade B-NHL have proved to be a useful molecular marker for monitoring minimal residual disease.
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PMID:Molecular pathways in low grade B-cell lymphoma. 957 Jun 87

Indolent lymphomas are a markedly heterogeneous group of lymphoproliferative disorders including B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mantle cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma. The molecular pathophysiology of indolent lymphoma is characterized by distinct genetic pathways which selectively associate with different clinico-pathologic categories of the disease. At diagnosis, B-cell chronic lymphocytic leukemia frequently display deletions of 13q14, trisomy 12 and alterations of the ATM gene, whereas evolution to Richter's syndrome is associated with disruption of p53. Lymphoplasmacytoid lymphoma carries t(9;14) (p13;q32) in approximately 50% of cases, leading to the deregulated expression of the PAX-5 gene. Follicular lymphoma consistently harbors rearrangement of BCL-2. With time, a fraction of follicular lymphoma accumulates mutations of p53 and of p16 and evolves into a high grade lymphoma. MALT-lymphoma frequently associates with alterations of API2/MLT and, in some cases, of p53, BCL-6 and BCL-10. Studies of genotypic and phenotypic markers of histogenesis have shown that mantle cell lymphoma and a fraction of B-CLL/SLL derive from naive B-cells, whereas follicular lymphoma, lymphoplasmacytoid lymphoma and MALT-lymphoma originate from germinal center (GC) or post-GC B-cells. The identification of distinct genetic categories of indolent lymphoma may help in the therapeutic stratification of these disorders. In addition, genetic lesions of indolent lymphoma provide useful molecular markers for disease monitoring by high sensitivity techniques.
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PMID:Molecular pathophysiology of indolent lymphoma. 1068 15

To investigate the role of the cell cycle regulators p21(Waf1), p27(Kip1), retinoblastoma (Rb), and cyclin D1 in Richter's transformation of chronic lymphocytic leukemia (CLL), we analyzed 19 CLL and eight Richter's syndrome (RS) tumors, previously characterized for p53 and ARF/INK4a abnormalities. p21(Waf1)immunohistochemical expression was negative in 12 of 15 CLL (80%), whereas it was moderate or strong in three of seven RS (43%). p21(Waf1) gene was in germline configuration in all the tumors analyzed. Four immunohistochemical patterns of p53 and p21(Waf1) expression were observed: (1) p53-/p21- in 10 of 15 CLL (67%), but only in two of six RS (33%); (2) p53+/p21+ in three CLL (20%) and two RS (33%); (3) p53-/p21+ in one RS; and (4) p53++/p21- in two CLL and one RS. Two p53+/p21+ CLL evolved into RS. p53 mutations clustered around the p53++/p21- (two CLL and one RS) and p53-/p21- (one CLL and one RS) tumors. While the majority of CLL displayed strong p27 immunoreactivity, RS tumors were constantly p27-negative. p27(Kip1) gene was in germline configuration in all the tumors analyzed. Most CLL cases were negative for Rb expression. In contrast, all RS exhibited strong Rb expression. Cyclin D1 overexpression was only detected in one CLL evolving into RS and one RS. In conclusion, a p53+/p21- immunohistochemical pattern is shown exclusively by p53-mutated CLL/RS. Additionally, our results suggest a possible implication of moderate/strong p21(Waf1) expression, loss of p27 expression, and cyclin D1 overexpression in the Richter's transformation of CLL.
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PMID:Multiple cell cycle regulator alterations in Richter's transformation of chronic lymphocytic leukemia. 1204 Apr 34

Chromosomal imbalances were examined by comparative genomic hybridization in 30 cases of B-cell chronic lymphocytic leukemia (CLL) at diagnosis, in sequential samples from 17 of these patients, and in 6 large B-cell lymphomas transformed from CLL [Richter's syndrome (RS)] with no available previous sample. The most common imbalances in CLL at diagnosis were gains in chromosome 12 (30%), and losses in chromosomes 13 (17%), 17p (17%), 8p (7%), 11q (7%), and 14q (7%). The analysis of sequential samples showed an increased number of chromosomal imbalances in 6 of 10 (60%) patients with clinical progression and in 2 patients with stable stage C disease. No karyotypic evolution was observed in four cases with stable stage A disease and in one RS clonally unrelated to the previous CLL. Gains of 2pter, and 7pter, and losses of 8p, 11q, and 17p were recurrent alterations associated with karyotype progression. RS showed a higher number of gains, losses, total alterations, and losses of 8p and chromosome 9 than CLL at diagnosis. 17p losses were associated with p53 gene mutations and with a significantly higher number of chromosomal imbalances than tumors with normal chromosome 17 profile. However, no relationship was observed between 9p deletions and p16(INK4a) gene alterations. Losses of 17p and an increased number of losses at diagnosis were significantly associated with a shorter survival. These findings indicate that CLL has frequent chromosomal imbalances, which may increase during the progression of the disease and transformation into large cell lymphoma. Genetic alterations detected by comparative genomic hybridization may also be of prognostic significance.
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PMID:Genetic imbalances in progressed B-cell chronic lymphocytic leukemia and transformed large-cell lymphoma (Richter's syndrome). 1221 24

We report the clinical, cytogenetic, fluorescence in situ hybridization (FISH) and molecular findings in a 54-yr-old male patient diagnosed with B-cell chronic lymphocytic leukemia (B-CLL), who showed progression to a diffuse large B-cell lymphoma (Richter's syndrome). Genetic studies were performed at diagnosis and during the Richter's transformation (RT). A clonal karyotype with two dicentric chromosomes, psu dic(12,21)(q24;q10) and dic(17,18)(p11.2;p11.2), was found. Both rearrangements were confirmed by FISH. Molecular cytogenetics analysis using p53 probe showed monoallelic loss of this tumor suppressor gene in 43.8% and 77.3% of cells for the first and the second studies, respectively). In both studies, deletions of D13S319 (18% and 12% of cells) and D13S25 loci (13% and 12% of cells) at 13q14 were found. Polymerase chain reaction analysis showed the MBR/JH rearrangement of the bcl-2 gene. FISH studies using LSI bcl-2/IgH probe allowed quantifying the clonal cell population with this rearrangement (4% and 6.6% of cells at diagnosis and RT, respectively). To our knowledge, this is the first case with a psu dic(12,21) described in B-CLL. The low percentage of cells with the 13q14 deletion and bcl-2/IgH rearrangement suggests that they were secondary events that resulted from clonal evolution. Our patient had a short survival (9 months) and a clear lack of response to several therapeutic agents, confirming the association of p53 gene deletion and karyotypic evolution with disease progression.
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PMID:Cytogenetic, FISH, and molecular studies in a case of B-cell chronic lymphocytic leukemia with karyotypic evolution. 1246 Feb 36


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