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B F Odermatt

Publications and source records attributed to B F Odermatt.

At least 19 recordsLinked to original sources
PubMed2001

The role of Epstein-Barr virus in neoplastic transformation.

In this review, we focus on new data from basic, translational and clinical research relating to the Epstein-Barr virus (EBV). Beside its well-known tropism for B lymphocytes and epithelial cells, EBV also infects T lymphocytes, monocytes and granulocytes. After primary infection, EBV persists throughout the life span in resting memory B cells, from where it is reactivated upon breakdown of cellular immunity. In the process of neoplastic transformation, the EBV-encoded latent membrane protein 1 (LMP1) oncogene represents the major driving force. LMP1 acts like a constitutively activated receptor of the tumor necrosis factor receptor family and allows the amplification or bypassing of physiological regulatory signals through direct and indirect interactions with proteins of the tumor necrosis factor receptor-associated factor (TRAF) family. TRAF2-mediated NF-kappaB activation, AP-1 induction and JAK3/STAT activation may result in sustained proliferation leading to lymphoma. The ability of LMP1 to suppress germinal center formation and its capacity to mediate its own transcriptional activation shed new light on the pathogenesis of EBV-associated latency type II lymphoproliferations like Hodgkin's disease and angioimmunoblastic lymphadenopathy. The carboxy terminus of LMP1 is also a reliable marker for individual EBV strain identification and thus offers new possibilities in tracing the molecular events leading to posttransplant lymphoproliferative disorders (PTLDs). Cytotoxic T lymphocytes directed against well-characterized epitopes of EBV latency genes represent an already successful and promising therapeutic approach to EBV-associated lymphomas, in particular PTLDs.

Apoptosis↗
PubMed2000

Loss of type VI collagen in experimental and most spontaneous human fibrosarcomas.

Expression of type VI collagen, an adhesive protein of mesenchymal tissues, is significantly down-regulated upon viral transformation of fibroblasts. Likewise, most cell lines derived from spontaneous mesenchymal tumors, including fibrosarcomas, rhabdomyosarcomas, leiomyosarcomas, chondrosarcomas and liposarcomas, do not synthesize type VI collagen because they are not capable of expressing all 3 of the polypeptide chains required for the assembly of a functional heterotrimeric molecule. When injected into nude mice, neither fibrosarcoma cells (HT1080) nor rhabdomyosarcoma cells (A204) initiate the synthesis of type VI collagen, suggesting that the inhibition is not caused by deficiency of a paracrine factor. Immuno-histochemical studies further illustrate that 15 of 17 spontaneous adult fibrosarcomas lack type VI collagen in the tumor stroma. The absence of this important adhesion protein may contribute to tumorigenicity, invasiveness and/or metastasis of mesenchymal tumor cells.

Adult↗
PubMed1999

Latent membrane protein 1 associated signaling pathways are important in tumor cells of Epstein-Barr virus negative Hodgkin's disease.

The latent membrane protein 1 (LMP1) oncogene of Epstein-Barr virus (EBV) is selectively expressed in the Reed-Sternberg (RS) cells of EBV-associated Hodgkin's disease (HD). However, no differences in clinical presentation and course are found between EBV positive and EBV negative forms of HD suggesting a common pathogenetic mechanism. We have studied the LMP1 associated signaling pathways and their dominant negative inhibition in the myelomonocytic HD-MyZ and the B-lymphoid L-428 HD cell lines. In both EBV negative cell lines expression of LMP1 is associated with the formation of multinuclear RS cells. Dominant negative inhibition of NF-kappa B mediated signaling at the step of I kappa B-alpha phosphorylation results in increased cell death with only a few typical RS cells resistant to overexpression of the dominant negative inhibitor I kappa B-alpha-N delta 54. However, dominant negative inhibition of NF-kappa B mediated signaling at the early step of TRAF2 interaction results in the formation of multinuclear cells in both cell lines and, in addition, in clusters of small mononuclear cells in the HD-MyZ cell line. In HD-MyZ cells overexpression of the powerful JBD-inhibitor of the JNK signal transduction pathway is restricted to small cells and never observed in RS cells. These small cells undergo apoptosis as shown by the TUNEL technique. Apoptosis of small cells is still observed after co-transfection of JBD and LMP1 but in addition a few apoptotic HD-MyZ cells with large fused nuclear masses are identified suggesting that specific inhibition of JNK leads also to apoptosis of LMP1 induced RS cells. Thus, activation of the JNK signaling pathway is also important in the formation of Reed-Sternberg cells. Our findings are consistent with a model where all three LMP1 associated functions, i.e. NF-kappa B mediated transcription, TRAF2 dependent signaling, and c-Jun activation act as a common pathogenetic denominator of both EBV negative and EBV positive HD.

Herpesvirus 4, Human↗
PubMed1997

Distribution pattern of tenascin-C in normal and neoplastic mesenchymal tissues.

Descriptions for tenascin-C distribution are largely restricted to epithelial tumours. The present study utilized newly developed and characterized monoclonal (hT191) and polyclonal antibodies to investigate the distribution pattern of tenascin-C in a panel of mesenchymal tumours, which was contrasted with normal tissue. The specific antibodies recognized the distinctive star-like hexabrachion protein isolated from transformed cell-culture medium and serum from normal individuals. In normal tissues, a strong tenascin-C expression in the extracellular matrix was largely restricted to basement-membrane regions of epithelium and tonsilar sinusoids, pericellularly within smooth-muscle bundles, associated with perimysial, -chondrial, -neurial and -tendon surfaces, and diffusely within vascular adventitia. It was found in the corresponding tumours of the neural sheath (schwannoma) and smooth muscle (leiomyosarcoma), and was abundantly present around certain blood vessels of mesenchymal tumours. Although not detected in normal muscle, or in adipose or fibrous connective tissue, neo-expression of tenascin-C was shown in more than half of the rhabdomyosarcomas, fibromas and liposarcomas, with an increased positive percentage in variably malignant myxoid liposarcomas compared with lipoma-like sarcomas. Tenascin-C was typically found in the extracellular matrix of soft-tissue tumours, but was notably absent from the epithelial-cell components of mixed epithelial/mesenchymal tumours. Its apparently enhanced expression in soft-tissue tumours differs from that of most other large extracellular-matrix proteins, suggesting possible functional involvement of the cell-adhesion molecule, tenascin-C, in the neoplastic phenotype.

Antibodies↗
PubMed1997

Natural 30 base pair and 69 base pair deletion variants of the LMP1 oncogene do stimulate NF-kappaB-mediated transcription.

An increasing number of reports shows a link between the Epstein-Barr virus (EBV) and lymphoid neoplasia. The latent membrane protein 1 (LMP1) is likely to play a determinant role in this process since this EBV encoded protein has oncogenic properties and is usually expressed in EBV-associated lymphoproliferative diseases (LPD), except Burkitt's lymphoma. We previously identified in LPD patients mutational hot spots and a 30 bp or 69 bp deletion in the LMP1 gene region coding for the C-terminal domain. These deletions are located in an area shown to be important for the activation of the transcription factor NF-kappaB. These findings lead us to test whether these natural deletion variants may have a functional effect. We measured the stimulation of their activity using a luciferase reporter plasmid containing NF-kappaB responsive elements. We tested the NF-kappaB inducing activity of four naturally occurring LMP1 deletion variants. Our results show that these deletion variants activate NF-kappaB to the same level as the wild-type form, indicating that the crucial residues for NF-kappaB activation are conserved among the variants isolated and lie within the last 32 amino acids of the C-terminal domain of the LMP1 oncogene.

Base Composition↗
PubMed1996

Expression and distribution of two alternatively spliced transcripts from the chicken alpha 2 (VI) collagen gene.

Two types of mRNA molecules with different 3' ends are transcribed from the chicken alpha 2(VI) collagen gene. The major splice variant encodes a polypeptide with a von Willebrand factor A domain at its carboxyl terminus. In the minor splice variant, this A domain is replaced by a novel motif which reveals some similarity to a fibronectin type III repeat. In situ hybridization experiments demonstrate that the major transcript is ubiquitously expressed. Substantial amounts are found in skeletal and cardiac muscle, gizzard, skin, tendon, liver, the wall of blood vessels, and the connective tissue of peripheral nerves. In contrast, the minor transcript is expressed at a very low level and can hardly be detected in any tissue by in situ hybridization. Only the aortic wall contains a considerable amount of this splice variant. However, no difference is observed by Northern blotting and the polymerase chain reaction in the ratio of the two transcripts when aorta and the other tissues are compared. Thus, the minor splice variant is not expressed in a tissue specific manner and, consequently, it is unlikely that it plays a tissue specific role. It might rather serve a general function in the structure and assembly of type VI collagen microfibrils.

Alternative Splicing↗
PubMed1996

Expression of the LMP1 oncoprotein in the EBV negative Hodgkin's disease cell line L-428 is associated with Reed-Sternberg cell morphology.

The latent membrane protein 1 (LMP1) oncogene is one of the major proteins synthesized by the Epstein-Barr virus (EBV) and is expressed in Reed-Sternberg (RS) cells of EBV-associated Hodgkin's disease (HD). We have studied the effect of this oncoprotein on the formation of RS cells in the EBV-negative HD cell lines L-428 and KM-H2 as well as on the formation of multinucleated cells in the mononuclear human embryonic kidney cell line 293. LMP1 prototype (B95-8) and its naturally occurring carboxy terminal 30 base pair deletion variant LMP1-del were transfected into the cell lines and cytocentrifuge preparations were analysed after 24, 48, 72, 144, 216, and 240 h. While no oncoprotein expression was seen in the KM-H2 cell lines, expression of LMP1 and LMP1-del was observed in the L-428 and 293 cell lines. In the HD cell line L-428 oncoprotein expression was infrequent but when observed was very strong and preferentially associated with multinucleated RS cell morphology (71% of LMP1 positive cells). This is in contrast with the untransfected or transfected but not expressing cells where intermediate mononuclear elements predominated over multinucleated RS cells (< 3%). Frequent oncoprotein expression was observed in the 293 cells and again was associated with multinuclearity. These LMP1 expressing 293 giant cells showed strong expression of ICAM-1(CD54), not detectable in the untransfected cells. In the LMP1-del transfectants giant cells with more than four nuclei were frequently observed. However, giant cells were much less frequent in 293 cells transfected with the amino terminal deletion variant of LMP1 or the lytic form of LMP1, known to induce low NF-kappa B activation compared to the LMP1 prototype. Therefore, LMP1 mediated NF-kappa B activation appears to be involved in polycaria formation. The strong association of LMP1 expression with multinuclearity in a genetically unstable condition -the L-428 and 293 cells show multiple chromosomal abnormalities-suggests that this oncoprotein including its naturally occurring carboxy terminal deletion variant promote the formation of multinuclear cells, in particular of RS cells in EBV-associated HD.

Blotting, Western↗
PubMed1996

Distribution of the large aggregating proteoglycan versican in adult human tissues.

We studied the distribution of the large hyaluronan-binding proteoglycan versican (also known as PG-M) in human adult tissues using affinity-purified polyclonal antibodies that recognize the core protein of the prominent versican splice variants VO and V1. Versican was present in the loose connective tissues of various organs and was often associated with the elastic fiber network. Furthermore, it was localized in most smooth muscle tissues and in fibrous and elastic cartilage. Versican staining was also noted in the central and peripheral nervous system, in the basal layer of the epidermis, and on the luminal surface of some glandular epithelia. In blood vessels, versican was present in all three wall layers of veins and elastic arteries. In muscular arteries the immunoreactivity was normally restricted to the tunica adventitia. However, it appeared in the media and the split elastica interna of atherosclerotically transformed vessel walls. Our survey of the distribution of versican in normal human tissues now forms the basis for extended studies of potentially aberrant versican expression during pathogenic processes.

Adult↗
PubMed1995

Mutational hot spots within the carboxy terminal region of the LMP1 oncogene of Epstein-Barr virus are frequent in lymphoproliferative disorders.

We have recently identified in Epstein-Barr virus (EBV) positive Hodgkin's disease (HD) a variant of the latent membrane protein 1 (LMP1) oncogene characterized by four point mutations and a 30 base pair deletion. These findings led us to test whether such mutants were also present in other lymphoproliferative disorders (LPD). We analysed 98 EBV DNA positive cases (67 LPD, 15 benign conditions, 16 lymphoblastoid cell lines) by PCR for deletions within the LMP1 gene. DNA sequencing of the region coding for the carboxy terminal protein domain was performed on 24 cases. In 13 cases the same combination of 4 point mutations at positions 168,320, 168,308, 168,295 and 168,225 was identified. Of these cases, 12 had an additional point mutation at position 168,357 and eight at position 168,355, and nine had a 30 base pair deletion including nucleotides 168,285 to 168,256. These deletion mutants were identified in HD, angioimmunoblastic lymphadenopathy, B-immunoblastic lymphoma, peripheral T-cell lymphoma, and two lymphoblastoid cell lines. Our findings reveal a high frequency of non-random point mutations at preferential sites within the 3' (carboxy terminal) region of the LMP1 oncogene. The association of these mutational hot spots with LPD suggests that they are involved in EBV related lymphomagenesis and that they define a clinically relevant EBV strain.

Antigens, Viral↗
PubMed1995

Occult hepatosplenic T-gamma delta lymphoma. Value of genotypic analysis in the differential diagnosis.

We report on a patient with a rare hepatosplenic gamma delta T-cell lymphoma (gamma delta TCL) presenting clinically with B-symptoms, hepatosplenomegaly and pancytopenia. During the initial stage of the disease the sparse malignant cells could not be detected histologically. Furthermore, their identification was obscured by massive macrophage proliferation with haemophagocytosis in the spleen. Diagnosis was established by detection of a clonal T-cell receptor (TcR) rearrangement and, retrospectively, by demonstration of rare cells expressing and aberrant T-cell phenotype. The findings in this patient emphasize that minimal neoplastic T-cell infiltrates can lead to severe clinical symptoms. Initial biopsy findings may be misinterpreted as benign. Gamma delta TCL may elaborate lymphokines that suppress haematopoiesis, leading to pancytopenia and macrophage proliferation.

Genotype↗
PubMed1995

A deletion mutant of the LMP1 oncogene of Epstein-Barr virus is associated with evolution of angioimmunoblastic lymphadenopathy into B immunoblastic lymphoma.

The latent membrane protein 1 (LMP1) oncogene is one of the major proteins synthesized by the Epstein-Barr virus (EBV). It is expressed in Reed-Sternberg cells of Hodgkin's disease (HD), tumor cells of nasopharyngeal carcinoma (NPC), and immunoblasts of angioimmunoblastic lymphadenopathy (AILD). A particular LMP1 deletion mutant was recently identified in NPC and clinically and histologically aggressive HD. We studied two patients with AILD that subsequently progressed into immunoblastic lymphoma (IBL) in order to investigate whether the LMP1 deletion mutant was implicated in progression of AILD into IBL. Immunohistology and in situ hybridization were performed on diagnostic biopsies. DNA extracted from fresh frozen material was used for rearrangement studies and polymerase chain reaction (PCR) based amplification and sequencing of portions of the LMP1 gene. Immunohistochemistry revealed B cell origin of both cases of IBL. In the first patient clonal rearrangement of the immunoglobulin heavy-chain gene was present in IBL but not in AILD. In this patient, scattered immunoblasts of AILD and numerous tumor cells of B-IBL were shown to contain EBV transcripts (EBER1) and to express LMP1. Sequence analysis of the LMP1 gene from AILD and IBL in the first, and from IBL in the second patient, revealed identical deletions and point mutations. This LMP1 deletion mutant is identical to those which have been reported in HD and NPC. Its association with evolution of AILD into B-IBL, aggressive HD and NPC, suggests that this particular mutant is more widespread than originally thought and is clinically relevant.

Adult↗
PubMed1994

Tissue-specific expression of the fibril-associated collagens XII and XIV.

Interstitial collagen fibrils form the supporting scaffold of all connective tissues. The synthesis of this framework is subject to a precise spatial and temporal regulation in order to meet the mechanical needs of every tissue type. A subgroup of non-fibrillar collagens termed FACIT seems to play a role in this regulation by providing specific molecular bridges between fibrils and other matrix components. Collagens XII and XIV represent such FACIT molecules and occur preferentially in tissues containing banded type I collagen fibrils. We have used the techniques of indirect immunofluorescence and in situ hybridization to investigate the expression patterns of the two molecules during chicken embryonic development. We detected specific differences in these patterns, which may be related to the respective functions of the two proteins within the connective tissues. Collagen XIV was expressed at very few sites in the 6-day-old embryo, but occurred in virtually every collagen I-containing tissue (skeletal muscle, cardiac muscle, gizzard, tendon, periosteum, nerve) by the end of embryonic development. In contrast, collagen XII was fairly abundant in the 6-day-old embryo but was, at later stages, restricted to only a few dense connective tissue structures (bone, tendon, gizzard). Thus, our results suggest that collagen XII and collagen XIV serve different functions during embryonic development although their structures are highly similar.

Animals↗
PubMed1994

Expression of human recombination activating genes (RAG-1 and RAG-2) in lymphoma.

Two recently discovered genes, the recombination activating genes 1 and 2 (RAG-1 and RAG-2), are necessary to perform variable (V), diversity (D), and joining (J) recombination. They synergistically activate VDJ recombination to generate immunocompetent lymphocytes. Disruption of either gene results in a maturation arrest at a very early B and T cell progenitor stage. Expression and downregulation of RAG's are closely associated with interleukin 7, sIgM and TCR-CD3 complex, respectively. Assessment of RAG mRNA expression is a valuable marker in identifying the genotypic maturation status of leukemias and lymphomas. Persistent RAG expression in otherwise mature lymphoid proliferations may explain puzzling biological and clinical observations such as multiple rearrangements in lymphomas with a mature phenotype. Lack of RAG expression in Hodgkin's disease with abundant Reed-Sternberg cells is consistent with a mature phenotype of the latter. Availability of a anti-RAG-1 monoclonal antibody in the near future will facilitate RAG analysis of lymphomas.

Animals↗
PubMed1994

[Internal deletions of the latent membrane protein oncogenes of Epstein-Barr virus in Hodgkin's disease are almost identical with those of Asiatic nasopharyngeal carcinoma].

The latent membrane protein (LMP) oncogene of the Epstein-Barr virus (EBV) is 1300 base pairs (bp) long and expressed in Hodgkin and Reed-Sternberg (HRS) cells of about 50% of Hodgkin's lymphomas and in tumor cells of about 60% of nasopharyngeal carcinomas (NPC). The LMP sequences of EBV variants isolated from two NPC (NPC 1510 and NPC CAO) have recently been published. Compared to the standard EBV sequence (EBV B95-8) they both show deletions of 30 bp near the 3' end. These mutations render the LMP oncogene more aggressive in NPC. In 52 Hodgkin's lymphomas expressing the LMP oncogene was amplified the coding sequence by the polymerase chain reaction. In five tumors deletions within the coding region for the intracytoplasmic LMP domain have been found. DNA sequencing revealed three 30 bp deletions almost identical to those observed in NPC 1510 and NPC CAO. In a forth case, a 70 bp deletion encompassing the regions of the 30 bp deletions was found. Histologically, all five tumors with such deletions showed abundant HRS cells. It is likely that these mutations of the LMP oncogene in a similar way as in NPC also favour the proliferation of HRS cells in Hodgkin's disease.

Amino Acid Sequence↗
PubMed1993

Deletions within the LMP1 oncogene of Epstein-Barr virus are clustered in Hodgkin's disease and identical to those observed in nasopharyngeal carcinoma.

This study of 52 European patients with Hodgkin's disease (HD) expressing the latent membrane protein 1 (LMP1) oncogene within diagnostic Hodgkin and Reed-Sternberg (HRS) cells was performed to detect LMP1 isolates carrying deletions and to characterize them at a molecular and histologic level. Deletions were identified in 5 cases, clustered near the 3' end of the LMP1 gene, and histologically associated with numerous HRS cells. DNA sequencing showed homology with the deletions seen in the Asian nasopharyngeal carcinoma (NPC) isolates CAO and 1510. Our findings suggest that partial deletions of the LMP1 oncogene, associated with aggressive behavior in NPC CAO and NPC 1510, occur at a particular localization and confer a proliferative phenotype to lymphoid cells in HD.

Adult↗
PubMed1993

Expression of human recombination activating genes (RAG-1 and RAG-2) in angioimmunoblastic lymphadenopathy and anaplastic large cell lymphoma of T-type.

In order to determine the genotypic maturation status of the proliferating lymphoid cells in angioimmunoblastic lymphadenopathy (AILD) and in anaplastic large cell lymphoma of T-type (T-ALC), recombinase activating gene (RAG-1 and RAG-2) expression was assessed in six AILD and five T-ALC cases using a sensitive reverse transcriptase (RT) and competitive (C) polymerase chain reaction (PCR). RAG transcripts were not detectable in nine cases with high proliferating activity, suggesting that in most cases the proliferating cells are derived from mature (rearranged) lymphocytes. However, low levels of RAG transcripts were detected in one AILD and one T-ALC case and are consistent with either an involvement of immature lymphoid precursors in the proliferating pool or a deregulated T-cell maturation pathway with persistence of RAG expression. An association between RAG gene expression and poor response to therapy is possible but has to be tested in larger prospective series.

Animals↗
PubMed1993

Familial primary gastric lymphoma.

Familial lymphoma is uncommon and is usually associated with various forms of hereditary immunodeficiencies. Primary gastric lymphomas that occurred in three adults from the same family, who had no overt immunodeficiency or cancer of non-lymphomatous origin, are reported. Two sisters presented with a low grade lymphoma of the mucosa associated lymphoid tissue type. Their father presented with a high grade form of later onset. All lymphomas have been phenotypically characterised as being of B cell origin. Epstein-Bar virus DNA was detected by polymerase chain reaction in the biopsy specimen of the high grade lymphoma but bcl-2/JH protooncogene rearrangement, t (14:18), was not identified in either the low or high grade lymphoma specimens tested.

Aged↗