Primary mediastinal B cell lymphoma (PMBL) is a diffuse large B cell lymphoma (DLCL) postulated to arise from noncirculating thymic B lymphocytes. Because of its distinctive clinical and ...morphological features and putative unique cellular origin, PMBL is generally considered a distinct clinicopathological entity. Little is known, however, about the molecular characteristics of PMBL. Therefore, we analyzed 16 PMBLs for molecular alterations involving the bcl-1, bcl-2, bcl-6, c-myc, H-ras, K-ras, N-ras, and p53 genes and for Epstein-Barr virus infection, which are commonly involved in lymphoid neoplasia. Employing a combination of Southern blotting and/or polymerase chain reaction and single-strand conformation polymorphism assays, we detected genetic alterations in 7 of the 16 (44%) PMBLs. Whereas the bcl-6 gene is rearranged in up to 45% of DLCLs, rearrangement of the bcl-6 gene was detected in only 1 of these 16 (6%) PMBLS. Point mutations of the 5' noncoding region of the c-myc gene were demonstrated in 3 other cases (19%), although c-myc gene rearrangements were not seen by Southern blotting. Missense point mutations of the p53 gene were identified in 3 additional PMBLs (19%). Alterations of the bcl-1, bcl-2, or ras genes and evidence of Epstein-Barr virus infection were not observed. In conclusion, a variety of molecular lesions occur in PMBLs and may be involved in their pathogenesis. This molecular genetic pattern bears little resemblance to that known for other B cell malignancies, including DLCL. In particular, the infrequent occurrence of bcl-6 gene rearrangement in PMBLs distinguishes them from other DLCLs of B cell origin, suggesting that PMBLs do not represent a distinct subtype of DLCL.
The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is a γ-2
herpesvirus that is implicated in the pathogenesis
of Kaposi's sarcoma, and of primary effusion
B-cell lymphomas (PELs). KSHV infects ...malignant and progenitor
cells of Kaposi's sarcoma and PEL,,, it encodes putative oncogenes,, and genes that may cause Kaposi's sarcoma pathogenesis by stimulating
angiogenesis,,,.
The G-protein-coupled receptor encoded by an open reading frame (ORF 74) of
KSHV is expressed in Kaposi's sarcoma lesions and in PEL, and stimulates signalling pathways linked to cell
proliferation in a constitutive (agonist-independent) way. Here we show that signalling by this KSHV G-protein-coupled receptor
leads to cell transformation and tumorigenicity, and induces a switch to an
angiogenic phenotype mediated by vascular endothelial growth
factor, an angiogenesis, and
Kaposi's-spindle-cell growth factor. We find that
this receptor can activate two protein kinases, JNK/SAPK and p38MAPK, by triggering
signalling cascades like those induced by inflammatory cytokines
that are angiogenesis activators and mitogens for Kaposi's
sarcoma cells and B cells. We conclude that the KSHV G-protein-coupled
receptor is a viral oncogene that can exploit cell signalling pathways to
induce transformation and angiogenesis in KSHV-mediated oncogenesis.
Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, is invariably present in Kaposi's sarcoma lesions,. KSHV contains several viral oncogenes and serological evidence suggests ...that KSHV infection is necessary for the development of Kaposi's sarcoma, but cellular transformation by this virus has not so far been demonstrated. KSHV is found in the microvascular endothelial cells in Kaposi's sarcoma lesions and in the spindle 'tumour' cells,, which are also thought to be of endothelial origin. Here we investigate the biological consequences of infecting human primary endothelial cells with purified KSHV particles. We find that infection causes long-term proliferation and survival of these cells, which are associated with the acquisition of telomerase activity and anchorage-independent growth. KSHV was present in only a subset of cells, and paracrine mechanisms were found to be responsible for the survival of uninfected cells. Their survival may have been mediated by upregulation of a receptor for vascular endothelial growth factor. Our results indicate that transformation of endothelial cells by KSHV, as well as paracrine mechanisms that are induced by this virus, may be critical in the pathogenesis of Kaposi's sarcoma.
The Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV–8), has been found to be present in a limited subset of lymphoproliferative disorders. Among these are the ...primary effusion lymphomas, formerly designated body cavity-based lymphomas, a rare type of malignant lymphoma which possesses an unusual set of clinical and biologic features, suggesting that they represent a distinct disease entity. This virus is also present in a large proportion of cases of multicentric Castleman's disease, particularly those associated with HIV–infection. In addition, KSHV has been implicated in the pathogenesis of multiple myeloma, where it has been identified in bone marrow adherent cells but not in the neoplastic myeloma plasma cell population. However, the latter finding remains controversial. The discovery of KSHV in a subset of malignant lymphomas has allowed the development of lymphoma cell lines which now serve as biological reagents for propagating the virus, as a substrate for serologic assays, and as a model system for pathobiologic studies. This review discusses the features of KSHV–associated lymphoproliferative disorders and the evidence supporting its role in the pathogenesis of these diseases.
Recent clinical, pathological, and molecular studies have increased our understanding of posttransplantation lymphoproliferative disorders (PT-LPDs). Studies have shown that the majority of PT-LPDs ...arising in bone marrow transplant recipients are of donor origin; however, the source (host or donor) of the lymphoid cells that make up PT-LPDs arising in solid organ transplant recipients has not been systemically investigated. In this study, 18 PT-LPDs occurring in 16 organ transplant recipients (13 heart, 2 kidney, 1 lung), 9 donor tissues (for 10 recipients), and 14 uninvolved recipient tissues (from 12 patients) were examined employing restriction fragment length polymorphism analysis to determine their host or donor origin. The PstI-digested DNAs were analyzed by Southern blot hybridization using two highly informative polymorphic probes that map to chromosome 21 (CRI-PAT-pL427-4) and chromosome 7 (CRI-PAT-pS194). All solid organ PT-LPDs with corresponding uninvolved recipient DNA showed identical hybridization patterns; none of the PT-LPDs exhibited a hybridization pattern that matched donor DNA. These findings suggest that the vast majority of PT-LPDs arising in solid organ transplant recipients, in contrast to those arising in bone marrow transplant recipients, are of recipient origin.
Kaposi sarcoma (KS) remains the most common AIDS-associated malignancy worldwide. In sub-Saharan Africa especially, this aggressive endothelial-cell tumor is a cause of widespread morbidity and ...mortality. Infection with Kaposi sarcoma-associated herpesvirus (KSHV) is now known to be an etiologic force behind KS and primary-effusion lymphoma (PEL). Over time, KSHV has pirated many human genes whose products regulate angiogenesis, inflammation, and the cell cycle. One of these, the KSHV vGPCR, is a lytic product that is a constitutively active homolog of the IL-8 receptor. Although it is considered a viral oncogene and causes KS-like lesions in mice, vGPCR expression results in cell-cycle arrest of KSHV-infected PEL cells. In the present study, we show that this arrest is mediated by p21 in a p53-independent manner; the resulting Cdk2 inhibition decreases the efficiency of chemical induction of KSHV lytic transcripts ORF 50 and 26. Importantly, Cdk2 activity is also essential for replication in other human herpesviruses. The ability of vGPCR to delay or abort KSHV replication may explain how despite being a lytic product, this potent signaling molecule has a vital role in tumor formation via its induction of various KS-associated cytokines.
Kaposi's sarcoma-associated herpesvirus (KSHV, also known as human herpesvirus 8, or HHV 8) is a virus that is consistently present in Kaposi's sarcoma and in primary-effusion (body-cavity-based) ...lymphomas, malignancies that occur frequently, but not exclusively, in AIDS patients. KSHV is a gamma herpesvirus with homology to herpesvirus Saimiri and Epstein-Barr virus, both of which can transform lymphocytes. Cloning of a KSHV genome fragment revealed the presence of an open reading frame encoding a putative G-protein-coupled receptor that is homologous to a G-protein-coupled receptor encoded by herpesvirus Saimiri and to human interleukin-8 receptors. Here we show that the KSHV G-protein-coupled receptor is a bona fide signalling receptor which has constitutive (agonist-independent) activity in the phosphoinositide-inositoltrisphosphate-protein kinase C pathway. Furthermore, the KSHV G-protein-coupled receptor stimulates cellular proliferation, making it a candidate viral oncogene.
Representational difference analysis was used to isolate unique sequences present in more than 90 percent of Kaposi's sarcoma (KS) tissues obtained from patients with acquired immunodeficiency ...syndrome (AIDS). These sequences were not present in tissue DNA from non-AIDS patients, but were present in 15 percent of non-KS tissue DNA samples from AIDS patients. The sequences are homologous to, but distinct from, capsid and tegument protein genes of the Gammaherpesvirinae, herpesvirus saimiri and Epstein-Barr virus. These KS-associated herpesvirus-like (KSHV) sequences appear to define a new human herpesvirus.
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