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Query: UNIPROT:P06889 (Mol)
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The molecular genetic hallmark of mantle cell lymphomas (MCL) is the reciprocal translocation t(11;14)(q13;q32) which juxtaposes the bcl-1 proto-oncogene to one of the joining segments of the immunoglobulin heavy chain gene. This translocation is very common in MCL and occurs in up to 70% of these malignancies. Due to the aggressive nature of MCL, markers identifying tumor progression and clinical outcomes are necessary. In this study we examined whether a corroborative relation exists between p53 mutations, bcl-1 translocation, and the proliferative fraction in MCL. We evaluated the proliferative fraction, p53 gene status, and bcl-1 translocation in 21 patients with confirmed MCL. Controls consisted of normal DNA and 7 B-cell lymphomas. Immunohistochemical detection of Ki-67 was used to assess proliferative activity while molecular techniques were used to detect p53 mutations and the bcl-1 gene translocation. Reactivity to the monoclonal antibody Ki-67 on neoplastic cells ranged from 5% to 40% in typical MCL cases. The bcl-1 gene translocation was detected by PCR in 48% (10/21) of MCLs while no rearrangements were detected by PCR in case control DNA. Screening exons 5-8 of the p53 gene for mutations did not identify a single mutation in any of the MCL cases. No correlation was found between p53 mutations, the presence of a bcl-1 translocation, and the proliferative activity of neoplastic MCL cells. We conclude that these markers may demonstrate independent events which occur during the pathogenesis of MCL.
Int J Mol Med 1999 Apr
PMID:Proliferative fraction, bcl-1 gene translocation, and p53 mutation status as markers in mantle cell lymphoma. 1008 8

The steady-state levels of mRNA for the poly(ADP-ribose)polymerase (PARP), c-myc, p53, and histone H3 genes were investigated in 31 high-grade B-cell lymphomas by northern blot analysis. The panel included 15 nodal large B-cell lymphomas, nine mediastinal large B-cell lymphomas, and seven sporadic Burkitt's lymphomas. The PARP mRNA level was significantly higher in lymphomas than in control tissues and corresponded with the amount of PARP protein, as assessed by immunoblot analysis in six samples. The level of PARP mRNA was positively correlated with that of p53 mRNA. No correlation was found between the mRNA expression levels of PARP and histone H3, suggesting that PARP expression levels are independent of the proliferation rate of neoplastic cells. In this setting, the strong correlation between PARP and p53 suggests that the high expression of PARP may be associated with ongoing DNA damage in high-grade lymphomas.
Mol Carcinog 1999 Aug
PMID:Correlation of poly(ADP-ribose)polymerase and p53 expression levels in high-grade lymphomas. 1044 32

The present study analyzes the efficiency of a combination of four immunoglobulin heavy chain (IgH) gene polymerase chain reaction (PCR) primer systems and a multiplex T-cell receptor gamma chain (TRG) gene PCR for detection of clonality in 409 samples (234 paraffin sections, 175 bone marrow aspirates) of different lymphomas. Using the four IgH PCR systems together, clonality was detected in all samples of B-cell chronic lymphocytic leukemias, hairy cell leukemias, common acute lymphoblastic leukemias, and Burkitt-like B-cell lymphomas. Clonality was detected in all bone marrow aspirates with lymphoplasmacytoid immunocytoma, mantle cell lymphoma, marginal zone B-cell lymphoma, and unclassifiable low-grade B-cell lymphomas. The combined IgH gene PCR approach allowed clonality detection in 78.2% of myelomas, 75% of Burkitt lymphomas, 74.4% of diffuse large B-cell lymphomas, 68.7% of follicular center lymphomas, 50% of posttransplant lymphomas, 28.6% of anaplastic large cell lymphomas, 29% of T-cell lymphomas, and 18.8% of Hodgkin diseases. The combination of the four IgH gene primer systems with the multiplex TRG gene PCR allowed detection of clonality in 84.2% of B-cell neoplasms, 92.1% of T-cell non-Hodgkin lymphomas, and 18.8% of Hodgkin diseases, which was much more efficient than single PCR protocols.
Diagn Mol Pathol 1999 Jun
PMID:Combined polymerase chain reaction approach for clonality detection in lymphoid neoplasms. 1047 82

Lym-1, an anti-MHC class II Ab, displayed a unique processing pathway after binding to the surface of Raji B-lymphoma cells, in which Fab-like fragments were gradually released into the medium. The fragments had reduced interchain disulfide bonds. Fragmentation was markedly reduced by inhibitors of intracellular catabolism, namely ammonium chloride, chloroquine and leupeptin. The capacity of the process was high, and fragmentation of approximately 5x10(6) Ab molecules per cell per day was measured directly, in what can be considered to be a minimum estimate. Five other Abs to the MHC class II antigen were tested similarly on Raji and on three other B-cell lymphomas: none showed the same high level of fragmentation seen with Lym-1 binding to Raji, but significant fragmentation did occur with some of the Abs, particularly EDU-1 and L243. The level of fragmentation depended on the cell line as well as on the particular Ab. The other 5 Abs were all catabolized, to low molecular weight material, much more extensively than Lym-1. Part of the difference between Abs can probably be attributed to the fortuitous, preferential labeling of Lym-1 on the light chain, since the data suggest that the Fc fragment is fully degraded while the Fab-like fragment is released into the supernatant. This pathway of Ab processing is likely to be related to the physiology of the MHC class II antigen, which recycles into a mildly proteolytic intracellular compartment.
Mol Immunol 1999 Aug
PMID:Processing of antibodies to the MHC class II antigen by B-cell lymphomas: release of Fab-like fragments into the medium. 1059 16

We have studied the expression of the three human acute myeloid leukemia (AML) genes in primary samples of non-Hodgkin's B-cell lymphomas in which translocations involving these loci were not present. We found a widespread expression of the three AML genes in all the lymphoma samples as well as in the purified normal B-lymphocytes. Thus, the presence of the three mRNAs "per se" does not allow the identification of the pathological status. However, AML1 showed a different transcription pattern in the neoplastic tissues with respect to the normal B-cells. The AML1b isoform proved to be peculiar to this lymphoma. Our data support the idea that qualitative and quantitative alterations of AML1 gene expression deriving from deregulating mechanisms other than translocations may be involved in this malignancy. The usage of two differently regulated promoters driving the expression of the transcripts AML1b and AML1c may be one of these mechanisms. Finally, we report the presence of a new alternatively spliced transcript in normal B-cells.
Blood Cells Mol Dis 2000 Jun
PMID:The expression pattern of the AML1 gene in non-Hodgkin's B-cell lymphomas and normal B lymphocytes. 1095 Sep 38

Studies of lymphoid neoplasms occurring in normal or genetically engineered mice have revealed parallels and differences to non-Hodgkin lymphomas (NHL) of humans. Some mouse lymphomas have strong histologic similarities to the human NHL subsets including precursor B- and T-cell lymphoblastic, small lymphocytic, splenic marginal zone, and diffuse large-cell B-cell lymphomas (DLCL); whether molecular parallels also exist is under study. Others mouse types such as sIg+ lymphoblastic B-cell lymphoma have no histologic equivalent in human NHL even though they share molecular deregulation of BCL6 with human DLCL. Finally, Burkitt lymphoma does not appear to occur naturally in mice, but it can be induced with appropriately engineered transgenes.
Blood Cells Mol Dis
PMID:Non-Hodgkin lymphomas of mice. 1135 82

The authors describe a reverse transcriptase in situ polymerase chain reaction (RT in situ PCR) method that allows the determination of B-cell clonality as defined by expression of kappa and lambda mRNA as well as the different VH families that comprise the entire heavy chain (IgH) sequence using paraffin-embedded, formalin-fixed tissue. Polyclonal expression of B-cell light and heavy chains was documented in two reactive lymph nodes and a spleen in the same histologic distribution as the B-cell marker CD20. Monoclonal expression of kappa versus lambda mRNA was documented in 11 cases of B-cell lymphoma and was corroborated in 5 cases by flow cytometry; each case showed monoclonal expression of IgH. The authors analyzed seven additional tissues where a definitive diagnosis of B-cell lymphoma could not be rendered based on histologic, immunohistologic. and clinical analysis. RT in situ PCR for IgH and kappa versus lambda expression differentiated the B-cell lymphomas (n = 2) from reactive B-cell processes (n = 3) and from two cases of B-cell-rich T-cell lymphoma. The described RT in situ PCR methodology allows routine determination of the monoclonal versus multiclonal expression patterns of B cells, which will facilitate the diagnosis of B-cell lymphomas and aid in understanding the pathogenesis of B-cell malignancies using archival, paraffin-embedded tissues.
Diagn Mol Pathol 2001 Sep
PMID:In situ determination of B-cell heavy chain and kappa/lambda light chain expression patterns: methodology and clinical utility. 1155 20

We have introduced DNA methyltransferase 1 (Dnmt1) mutations into a mouse strain deficient for the Mlh1 protein to study the interaction between DNA mismatch repair deficiency and DNA methylation. Mice harboring hypomorphic Dnmt1 mutations showed diminished RNA expression and DNA hypomethylation but developed normally and were tumor free. When crossed to Mlh1(-/-) homozygosity, they were less likely to develop the intestinal cancers that normally arise in this tumor-predisposed, mismatch repair-deficient background. However, these same mice developed invasive T- and B-cell lymphomas earlier and at a much higher frequency than their Dnmt1 wild-type littermates. Thus, the reduction of Dnmt1 activity has significant but opposing outcomes in the development of two different tumor types. DNA hypomethylation and mismatch repair deficiency interact to exacerbate lymphomagenesis, while hypomethylation protects against intestinal tumors. The increased lymphomagenesis in Dnmt1 hypomorphic, Mlh1(-/-) mice may be due to a combination of several mechanisms, including elevated mutation rates, increased expression of proviral sequences or proto-oncogenes, and/or enhanced genomic instability. We show that CpG island hypermethylation occurs in the normal intestinal mucosa, is increased in intestinal tumors in Mlh1(-/-) mice, and is reduced in the normal mucosa and tumors of Dnmt1 mutant mice, consistent with a role for Dnmt1-mediated CpG island hypermethylation in intestinal tumorigenesis.
Mol Cell Biol 2002 May
PMID:DNA methyltransferase deficiency modifies cancer susceptibility in mice lacking DNA mismatch repair. 1194 Jun 49

Several types of genetic aberrations including microsatellite instability (MSI), allelic imbalance (AI), and chromosomal trisomies have been reported in low-grade (LG) mucosa-associated lymphoid tissue (MALT)-type gastric lymphomas. Presence of such genetic alterations could be a discriminator between de novo large cell lymphoma and high-grade (HG) MALT-type lymphoma. We investigated 17 primary gastric large B-cell lymphomas with and without features of MALT-type lymphoma for MSI, AI, and presence of trisomy of chromosomes 3, 12, and 18. We studied resection specimens from 17 primary gastric extranodal diffuse large B-cell lymphomas. Cases classified as HG MALT-type lymphoma, based on either the presence of LG MALT-type lymphoma component in the background (L/H MALT) or large cell lymphoepithelial lesions (HG MALT), and diffuse large B-cell lymphoma (DLBCL-NOS) when no features of MALT were present. MSI was analyzed using fluorescently labeled polymerase chain reaction primers (D3S11, D6S262, D3S1261, D3S1262, D3S1265). Paired tumor and normal DNA samples were amplified, and PCR products were analyzed on a DNA sequencer (ABI PRISM 373XL) with GeneScan (Applied Biosystems, Foster City, CA). MSI was defined as a gain of a novel-length allele compared with the corresponding normal tissue. AI was assessed at locus 3q27 (D3S1262 and D3S1265). The cases were analyzed for the presence of trisomy of chromosomes 3, 12, and 18 using interphase fluorescence in situ hybridization. MSI was detected in 4 out of 15 (27%) cases from which DNA was amplifiable with all primers and all MALT-type lymphomas. In two cases (13%), MSI was present at two loci sufficient to be classified as high-frequency MSI (MSI-H); this was seen exclusively in HG MALT lymphomas (P = 0.04). In the remaining two cases, MSI was detected at a single locus (low-frequency MSI). Allelic imbalance at the locus D3S1262 was detected in 4 out of 17 (24%) cases. It occurred more commonly in stage IE lymphomas when compared with higher stages (P = 0.03), regardless of lymphoma subtype. Trisomy 12 was detected in 3 out of 17 cases (18%) exclusively in stage IE lymphomas (P = 0.08). MSI was uncommon and was found exclusively in MALT-type lymphomas. MSI-H was even less common but occurred in HG MALT lymphomas only. Allelic imbalance at 3q27 (D3S1262) and trisomy 12 were found more commonly in low-stage disease. The latter two findings are in concordance with the recent suggestion that the published variation in gain of chromosomal material in high-grade gastric lymphomas may be related to stage rather than to the subtype of lymphoma. Because of the relatively low frequency of MSI in the high-grade B-cell lymphomas of the stomach, this feature cannot be used to reliably discriminate between the histologic types of extranodal diffuse large B-cell lymphoma.
Diagn Mol Pathol 2002 Jun
PMID:Diffuse large B-cell lymphoma of the stomach: assessment of microsatellite instability, allelic imbalance, and trisomy of chromosomes 3, 12, and 18. 1204 10

The t(14;18) is the most common genetic alteration in follicular lymphoma, and is detectable in a subset of diffuse large B-cell lymphomas (DLBCL), resulting in over-expression of the anti-apoptotic protein BCL-2. Although the t(14;18)-induced over-expression of BCL-2 is an important step in lymphomagenesis, this aberration alone is not sufficient to produce malignant lymphoma. Further analysis of these tumors is needed to identify additional genes that might be involved in the genesis of follicular lymphoma and progression to DLBCL. To address this issue, we analyzed the gene expression profiles of four t(14;18)-positive cell lines and two t(11;14)-positive mantle-cell lymphoma cell lines using cDNA microarrays containing 4364 genes, and compared them to the genetic profile of phenotypically purified B-cells obtained from hyperplastic tonsils. A total of 137 genes were differentially expressed by approximately twofold or more in the t(14;18) cell lines relative to tonsillar B-cells. 68 genes were up-regulated, 69 genes were down-regulated, and approximately 20% of the differentially regulated genes had no known function. The up-regulated genes included a number of genes involved in the promotion of cellular proliferation and survival, as well as cell metabolism. Down-regulated genes included mediators of cell adhesion and negative regulators of cell activation and growth. Hierarchical clustering analysis separated the t(14;18) and mantle-cell lines into distinct groups based on their gene expression profiles. We confirmed the differential expression of approximately 80% of selected up- and down-regulated genes identified by microarray analysis by quantitative real-time fluorescence reverse transcriptase polymerase chain reaction (RT-PCR) analysis and/or immunoblotting. This study demonstrates the utility of cDNA microarray analysis for the assessment of global transcriptional changes that characterize t(14;18)-positive cell lines, and also for the identification of novel genes that could potentially contribute to the genesis and progression of non-Hodgkin's lymphomas with this translocation.
J Mol Diagn 2002 Aug
PMID:Microarray analysis of B-cell lymphoma cell lines with the t(14;18). 1216 73


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