Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Caspases are cysteine proteases essential to apoptosis. We have identified two families of caspase-like proteins, Paracaspases (found in metazoans and Dictyostelium) and metacaspases (found in plants, fungi, and protozoa). Metazoan paracaspase prodomains contain a death domain and immunoglobulin domains. Several plant metacaspase prodomains contain zinc finger motifs resembling those in the plant hypersensitive response/cell death protein Isd-1. The human paracaspase prodomain binds Bcl10, a protein involved in the t(1;14)(p22;q32) translocation of mucosa-associated lymphoid tissue (MALT) lymphoma. Another MALT lymphoma translocation, t(11;18)(q21;q21), fuses the IAP-2 gene to the MLT1/MALT1 locus, which encodes the human paracaspase. We find that this fusion activates NF-kappaB and that the caspase domain is required for this function, since mutation of the conserved catalytic cysteine attenuates NF-kappaB activation.
Mol Cell 2000 Oct
PMID:Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. 1109 Jun 34

Arbitrarily primed PCR (AP-PCR) is a unique method to identify the cancer cell specific losses and gains of chromosomal regions by targeting specific genes or chromosomal segments. In the present study, introducing the AP-PCR technique with a single primer, we have ascertained the gains and losses of DNA fingerprints in 15 MALT lymphoma samples. Out of 15 prominent DNA fingerprints, the signal intensity of two fingerprints, labeled bands G and I, were significantly lower in 40 and 50% of tumors as compared to adjacent normal DNA fingerprints, respectively. Similarly, gains of signal intensity of DNA fingerprints (bands A and C) were detected in 13% of tumor samples studied. Variations in signal intensities were also found in other bands within a few samples. Although, the functional importance of these bands is unknown, this study indicates that the AP-PCR generated under or over amplified DNA fingerprints may participate during the progression of MALT lymphoma in human stomach. Moreover, these studies also suggest that the AP-PCR technique, with different primers, can be utilized for the determination of new chromosomal segments in MALT lymphoma samples that can be used for the identification of these diseases.
Int J Mol Med 2001 Mar
PMID:Identification of genomic imbalances in gastric MALT lymphoma using arbitrarily primed PCR DNA fingerprinting. 1117 14

Structural alterations in the meshwork of follicular dendritic cells (FDCs) are frequently found in malignant lymphomas. Formaldehyde fixation and paraffin embedding, however, have long prevented consistent detection of FDCs. Wet heat-induced epitope retrieval in Dako Target Retrieval Solution (TRS) (pH 6.0) enabled the reliable detection of FDCs through CD21, CD23, and CD35 antigens in routinely processed tissues from 11 reactive and 69 neoplastic lymphoproliferations, thus allowing the distribution of the FDCs to be reevaluated. Germinal center FDCs in lymphoid hyperplasias and expanded FDC meshworks in the 8 mantle cell lymphomas, 7 low-grade MALT lymphomas, and 6 low-grade follicular lymphomas were intensely stained with all these markers. In 6 cases of B cell chronic lymphocytic leukemia, tumor cells were CD23+. In four cases of nodular lymphocyte predominance Hodgkin's disease (HD), expanded FDC meshwork's sharply delineating negative tumor cells and their rosetting T cell, were revealed mainly with the CD21 and CD35 antibodies. Follicular dendritic cells were also demonstrated in 11 cases of grade I nodular sclerosing HD, including follicular HD. Striking dendritic cell clusters were revealed with all 3 antibodies in 9 angioimmunoblastic T cell lymphomas. Sparse or no FDC meshworks were detected in the 4 cases of grade II nodular sclerosing HD, 5 follicular lymphomas with high-grade transformation, and 5 T cell-rich B cell lymphomas. CD35 immunostaining showed the most consistent labeling in the four FDC sarcomas studied in the current article. Reproducible demonstration of FDCs in routinely processed paraffin sections with CD21, CD23, and CD35 antibodies, as presented here, provides invaluable pieces of information in the diagnosis of lymphoproliferative disorders.
Appl Immunohistochem Mol Morphol 2001 Jun
PMID:Follicular dendritic cells in reactive and neoplastic lymphoid tissues: a reevaluation of staining patterns of CD21, CD23, and CD35 antibodies in paraffin sections after wet heat-induced epitope retrieval. 1139 28

The authors studied 46 primary gastric lymphomas for expression of the p53 gene by immunohistochemistry and screened for mutations in p53 exon 5-8 by polymerase chain reaction-single strand conformation polymorphism. Twenty-five specimens cases were also analyzed for loss of heterozygosity (LOH) of chromosomal region 17p12-13.1. In 36 lymphomas negative for Epstein-Barr virus (EBV) infection, of which 29 were of mucosa-associated lymphoid tissue (MALT) type, p53 genetic changes were found in 47.2% but correlated poorly with overexpression. Only 20% of the mutations involved exon 7. There were recurrent mutations of intron 7, intron 6, and exon 6. In contrast, the 10 EBV-positive cases, none of MALT type, had a much higher rate of mutation, and all showed both p53 overexpression and p53 mutation and/or LOH, and 87.5% had mutations involving exon 7. Four of these involved codon 242, not seen in the EBV-negative group. Splicing mutations of intron 8 were seen in three specimens, two involving the same nucleotide position. In four of five specimens, LOH analysis identified microsatellite instability, allelic loss, or both. The Helicobacter pylori infection rate in the EBV-positive group (20%) was much lower than in the EBV-negative group (91.7%). These differences between the two groups suggest involvement of different carcinogens. Mutation of codon 242 has not been specifically associated with other tumors and may represent a mutational hot spot in the EBV-positive lymphomas.
Diagn Mol Pathol 2001 Sep
PMID:Epstein-Barr virus-associated gastric lymphomas are distinct from mucosa-associated lymphoid tissue-type lymphomas: genetic abnormalities of p53 gene. 1155 17

t(11:8) is a recurrent chromosomal abnormality observed in mucosa-associated lymphoid tissue (MALT)-type lymphoma. API2 and MLT genes have been implicated. The authors devised a dual-color interphase fluorescence in situ hybridization (FISH) system to detect splitting of 11q22 and its fusion with 18q21. Subjects were 44 cases of extranodal lymphoma and cases of primary macroglobulinemia. Whenever RNA was available, reverse transcriptase-polymerase chain reaction followed by sequence analysis was performed. Positive cases by dual-color FISH analysis were restricted to MALT-type lymphoma and one case of primary macroglobulinemia. Among 24 cases of MALT-type lymphoma, 14 (58%) (4 gastric, 5 pulmonary, 3 orbital, 1 salivary, and 1 thyroid lymphomas) had splitting of the 11q22 region probes and fusion of signals suggesting the translocation of chromosome 11 and 18. Reverse transcriptase-polymerase chain reaction analysis showed the API2/MLT gene fusion in 9 of 10 cases. Sequence analyses showed three different modes of involvement of the MLT gene, whereas the breakpoint at API2 was the same. Monoclonal component of serum immunoglobulin M was observed in 3 of 14 positive cases for the translocation. Direct visualization using dual-color FISH on samples serves as a molecular tool for management of MALT-type lymphoma with API2/MLT gene fusion.
Diagn Mol Pathol 2001 Dec
PMID:Detection of t(I 1; 18) in MALT-type lymphoma with dual-color fluorescence in situ hybridization and reverse transcriptase-polymerase chain reaction analysis. 1176 10

The Bcl10 gene was recently isolated from the breakpoint region of t(1;14)(p22;q32) in mucosa-associated lymphoid tissue (MALT) lymphomas. Somatic mutations of Bcl10 were found in not only t(1;14)-bearing MALT lymphomas, but also a wide range of other tumors. To clarify the actual frequency and spectrum of Bcl10 mutations in primary malignant chondrogenic tumors, we examined 89 cases of malignant chondrogenic tumors comprising 17 conventional chondrosarcomas, 33 mesenchymal chondrosarcomas, and 39 clear cell chondrosarcomas. Polymerase chain reaction single-stranded conformation polymorphism and sequencing analyses were done. No Bcl10 mutations were found in our series of malignant chondrogenic tumors. While screening for mutations, we also found three polymorphisms at codons 8 exon 1 of the Bcl10 gene. Our results strongly suggest that somatic mutations of Bcl10 are extremely rare in malignant cartilaginous tumors and do not commonly contribute to their molecular pathogenesis.
Int J Mol Med 2002 Mar
PMID:Lack of Bcl10 mutations in malignant cartilaginous tumors. 1183 26

Helicobacter pylori infection has been implicated in the development of gastrointestinal malignancy in adults and children. The histopathological processes that lead to such development are unknown. We compared the immune cell repertoire of mucosal lymph follicles in children with H. pylori infection to B cell type mucosal associated lymphoid tissue (MALT)-lymphoma of adults. The B and T cell populations residing within the lymph follicles and/or within B cell type MALT lymphoma were characteriZed by an immunohistochemical technique, utilizing B and T cell markers including: CD3, CD4, CD8 (T cells); CD20, CD40, GD74, BLA36, CD80, CD86 (B cells). Stain intensity was compared between the samples. T cell repertoire was observed within the lymph follicles, but not in the B cell MALT-lymphoma specimens. No significant difference was observed between the staining of CD40, CD74, CD8, and BLA36. The B cell markers, CD80 and CD86, were found within the centrocytic zone of the lymph follicle. In the B cell repertoire, no significant difference was observed between the lymph follicles of children with H. pylori infection and the adult MALT-lymphoma specimens except in CD20. B and T cells were in close anatomical proximity, enabling them to interact and exchange immunological information.
Pediatr Pathol Mol Med
PMID:T and B cell repertoire in gastric lymph follicles in children with Helicobacter pylori infection. 1184 77

Helicobacter pylori is implicated in the pathogenesis of gastritis and duodenal ulcers, gastric lymphoma of the mucosa-associated lymphoid tissue (MALT) type, and gastric adenocarcinoma. Eradication of H. pylori with antibiotic therapy therefore is essential, not only for the successful treatment of active gastritis, but also for the treatment and prevention of the MALT lymphoma. It has been suggested recently that immunostaining for H. pylori is more sensitive than special stains for the detection of the organism in the gastric biopsies after triple therapy. Fifty-five endoscopic mucosal biopsies from 38 patients, including 18 treated with H. pylori eradication therapy, were selected for immunostaining because they were either negative or contained rare H. pylori organisms by thiazine stain. Formalin-fixed, paraffin-embedded tissue sections were immunostained for H. pylori using a polyclonal antibody using standard immunoperoxidase technique. The results were compared with those obtained with the thiazine stain. Detection of H. pylori by immunostaining was easier and less time-consuming than by thiazine stain. There was complete agreement between immunostaining and thiazine stain in 48 (87%) cases. Of the 7 discordant cases, 3 (42%) were positive for H. pylori with thiazine only and 4 (48%) with immunostaining only. Given the nature of the selection of the study sample (absent to rare by thiazine stain), the discordance most likely represents a sampling error. The authors concluded that immunostaining for H. pylori did not appear to be more sensitive than special stains. Three cases with bacterial clumps were diagnosed previously as positive for H. pylori, but identified correctly as negative using both staining methods. Pathologists, however, should balance the added cost to patients of immunostaining against the time saved by the easier screening of the immunostained slides and the possibility of false positive results when special stains are interpreted by inexperienced pathologists.
Appl Immunohistochem Mol Morphol 2002 Mar
PMID:Is immunostaining for Helicobacter pylori superior to the special stain thiazine in detecting small numbers of H. pylori in gastric biopsies? 1189 42

The interpretation of clonality within H. pylori-associated gastritis and low-grade MALT lymphoma remains controversial. Due to the observation of MALT lymphoma regression after H. pylori eradication, new definitions concerning the border between benign reactive lesions and malignant gastric lymphoma are needed. Gene rearrangements for immunoglobulin heavy-chain in low-grade MALT lymphoma (N= 12) and H. pylori-associated chronic gastritis with lymphatic hyperplasia (N= 13) were analyzed by microdissection and polymerase chain reaction. Furthermore, T cell receptor-gamma chain rearrangements were analyzed by gene scan analysis. In 11 of 12 cases with initial low-grade MALT lymphoma, intraepithelial and subepithelial B cell rearrangements showed a restricted usage of the immunoglobulin heavy-chain 3. In H. pylori-associated chronic gastritis, the intraepithelial B cell compartment showed an oligoclonal the immunoglobulin heavy-chain rearrangement pattern with a predominance of VH3. The subepithelial compartment did not show any restrictive immunoglobulin heavy-chain gene usage. Additionally a mono- to oligoclonal rearrangement pattern of the T cell receptor-y chain was observed in low-grade MALT lymphoma, whereas an oligoclonal pattem was observed in chronic gastritis. Our data provide evidence that low-grade MALT lymphoma may start within the epithelium and subsequently infiltrate the subepithelial compartment. The observation of a mono- to oligoclonal TCR-gamma rearrangement suggests that an antigen selecting process also takes place within reactive T cells. Combining TCR-gamma gene scan analysis with IgH chain rearrangement analysis might help in discriminating between chronic gastritis and initial MALT lymphoma in questionable cases.
Cell Mol Biol (Noisy-le-grand) 2002 May
PMID:Compartment analysis of T cell receptor gamma--and immunoglobulin V(H) rearrangements by microdissection in patients with malt lymphoma and chronic gastritis with lymphatic hyperplasia. 1203 Apr 29

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


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