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E Cesarman

Publications and source records attributed to E Cesarman.

At least 37 records · Page 2Linked to original sources
PubMed1998

BCL-6 gene mutations in posttransplantation lymphoproliferative disorders predict response to therapy and clinical outcome.

Posttransplantation lymphoproliferative disorders (PT-LPDs) represent a heterogeneous group of Epstein-Barr virus-associated lymphoid proliferations that arise in immunosuppressed transplant recipients. Some of these lesions regress after a reduction in immunosuppressive therapy, whereas some progress despite aggressive therapy. Morphological, immunophenotypic, and immunogenotypic criteria have not been useful in predicting clinical outcome. Although structural alterations in oncogenes and/or tumor suppressor genes identified in some PT-LPDs correlate with a poor clinical outcome, the presence of these alterations has not been a consistently useful predictor of lesion regression after reduction of immunosuppression. We examined 57 PT-LPD lesions obtained from 36 solid organ transplant recipients for the presence of mutations in the BCL-6 proto-oncogene using single-strand conformation polymorphism and sequence analysis, followed by correlation with histopathologic classification and clinical outcome, which was known in 33 patients. BCL-6 gene mutations were identified in 44% of the specimens and in 44% of the patients; none were identified in the cases classified as plasmacytic hyperplasia. However, mutations were present in 43% of the polymorphic lesions and 90% of the PT-LPDs diagnosed as non-Hodgkin's lymphoma or multiple myeloma. BCL-6 gene mutations predicted shorter survival and refractoriness to reduced immunosuppression and/or surgical excision. Our results suggest that the BCL-6 gene structure is a reliable indicator for the division of PT-LPDs into the biological categories of hyperplasia and malignant lymphoma, of which only the former can regress on immune reconstitution. The presence of BCL-6 gene mutations may be a useful clinical marker to determine whether reduction in immunosuppression should be attempted or more aggressive therapy should be instituted.

Cell Transformation, Neoplastic↗
PubMed1998

Transformation of primary human endothelial cells by Kaposi's sarcoma-associated herpesvirus.

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.

Antigens, Viral↗
PubMed1998

Demonstration of Kaposi's sarcoma-associated herpes virus cyclin D homolog in cutaneous Kaposi's sarcoma by colorimetric in situ hybridization using a catalyzed signal amplification system.

Kaposi's sarcoma-associated herpes virus (KSHV)/human herpes virus 8 (HHV8) DNA sequences have been demonstrated in Kaposi's sarcoma (KS), as well as in some acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (NHL) and in multicentric Castleman's disease. Although KSHV DNA generally is abundant in KSHV-associated lymphomas, few copies of the virus are present in KS, a property that confounds detection by in situ methods. Previous in situ studies, which identified KSHV in lesions of KS, relied on the use of polymerase chain reaction (PCR) to amplify target DNA sequences before in situ hybridization (ISH) for localization or used ISH with radioactively-labeled probes to obtain adequate levels of detection sensitivity. In this study, a novel nonisotopic nucleic acid ISH method using catalyzed signal amplification and colorimetric detection without PCR-dependent target amplification was used to identify KSHV-specific sequences. The level of sensitivity was increased further by using a probe that detects viral cyclin D homolog transcripts, which are expressed at significant levels during latent viral infection. Thirty cutaneous lesions of KS (25 AIDS-related and five classical European type) were evaluated. AIDS-related NHL and cell lines derived from patients with AIDS-related NHL, all of which were known to harbor KSHV by Southern blot analysis, were used as positive controls. NHL and benign cutaneous vascular lesions not associated with AIDS were used as negative controls. For each of the 30 KS lesions studied, hybridization signals were detected in most of the spindle cells surrounding the atypical slit-like vascular channels and also were detected in some endothelial cells in well-formed blood vessels in the perilesional dermis. Plaque and nodular lesions generally contained more labeled cells than did early patch lesions. All AIDS-related NHL and cell lines contained KSHV-specific sequences; however, the non-AIDS-related NHLs and benign vascular lesions were negative. These results confirm the presence of KSHV sequences in cutaneous KS and provide in situ evidence of infection by this virus in early patch-stage lesions. This study also defines the in situ expression of the KSHV cyclin D homolog viral oncogene in cutaneous KS. The use of this sensitive nonisotopic ISH method should allow detection of other KSHV-specific gene products, further defining the pathobiology of this virus.

3,3'-Diaminobenzidine↗
PubMed1998

The morphologic and molecular genetic categories of posttransplantation lymphoproliferative disorders are clinically relevant.

BACKGROUND: Posttransplantation lymphoproliferative disorders (PT-LPDs) are a well-known complication of immunosuppression associated with solid organ transplantation. The clinical course of PT-LPDs is unpredictable; some patients experience regression of all lesions with a reduction in immunosuppression, whereas other patients, despite chemotherapy, radiation therapy, or surgery, rapidly die of their disease. In this study, the authors attempted to establish whether the previously described morphologic and molecular genetic categories of PT-LPD--plasmacytic hyperplasia (PH), polymorphic PT-LPD (polymorphic), and malignant lymphoma/multiple myeloma (ML/MM)--are clinically relevant and helpful in predicting the clinical outcome of patients who develop these lesions. METHODS: To determine the clinical significance of the morphologic and molecular genetic categories of PT-LPDs, the clinical characteristics of 32 solid organ transplant recipients (26 heart, 5 kidney, and 1 lung), including age, time from transplantation to development of PT-LPD, stage of disease, and clinical outcome, were compared with the morphologic and molecular genetic features of the 41 PT-LPDs that they developed (15 PH in 12 patients, 19 polymorphic in 16 patients, and 7 ML/MM in 6 patients). Clinical outcome was defined by the following categories: 1) regression (after a reduction in immunosuppression) and surgical resolution (by surgical excision, with or without a reduction in immunosuppression); 2) medical resolution (by chemotherapy and/or radiation therapy); and 3) no response. RESULTS: Although there was no difference in the time from transplantation to PT-LPD development among patients belonging to the three morphologic and molecular genetic categories, there was a significant difference in patient age at the time of PT-LPD development (P < 0.0098). Younger patients developed PH (mean age of 19 years), whereas older patients developed polymorphic PT-LPD (mean age of 35 years) and ML/MM (mean age of 56 years). Patients with PH presented with lower stages of disease (Stages I-II) than patients with ML/MM (P < 0.0004). Furthermore, there was a statistically significant trend between morphologic and molecular genetic category and clinical outcome, with decreased likelihood that lesions categorized as PH, polymorphic, or ML/MM would regress with a reduction in immunosuppression or be resolved by surgery, whereas those classified as ML/MM were more likely to exhibit no response to aggressive clinical intervention (P < 0.00006). Furthermore, no patients with PH died, whereas 20% with polymorphic PT-LPD and 67% with ML/MM died as a direct result of their PT-LPDs. CONCLUSIONS: This study strongly suggests that classification of PT-LPDs into the morphologic and molecular genetic categories PH, polymorphic, PT-LPD and ML/MM is clinically relevant.

Adult↗
PubMed1998

Inhibition of constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor by protein kinases in mammalian cells in culture.

Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8, which is consistently present in tissues of patients with Kaposi's sarcoma and primary effusion lymphomas, contains a gene that encodes a G protein-coupled receptor (KSHV-GPCR). We recently showed that KSHV-GPCR exhibits constitutive signaling via activation of phosphoinositide-specific phospholipase C and stimulates cell proliferation and transformation. In this study, we determined whether normal cellular mechanisms could inhibit constitutive signaling by KSHV-GPCR and thereby KSHV-GPCR-stimulated proliferation. We show that coexpression of GPCR-specific kinases (GRKs) and activation of protein kinase C inhibit constitutive signaling by KSHV-GPCR in COS-1 monkey kidney cells and in mouse NIH 3T3 cells. Moreover, GRK-5 but not GRK-2 inhibits KSHV-GPCR-stimulated proliferation of rodent fibroblasts. These data provide evidence that cell regulatory pathways of receptor desensitization may be therapeutic targets in human diseases involving constitutively active receptors.

3T3 Cells↗
PubMed1998

G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator.

The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is a gamma-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.

3T3 Cells↗
PubMed1998

Immunoglobulin VH gene mutational analysis suggests that primary effusion lymphomas derive from different stages of B cell maturation.

Primary effusion lymphoma (PEL) is a recently described distinct subtype of non-Hodgkin's lymphoma associated with infection by the Kaposi's sarcoma-associated herpesvirus, also called human herpesvirus-8. Most cases of PEL are also associated with the Epstein-Barr virus (EBV). In order to better characterize the cellular origin of PEL, we investigated the immunoglobulin (Ig) heavy chain variable region (VH,) genes expressed by tumor cells of the BC-1 and BC-3 cell lines derived from PELs and five original PEL specimens. In the six EBV-positive PELs examined, including the BC-1 cell line, the expressed VH gene sequences showed numerous point mutations relative to the putative germline VH gene sequences. In addition, the VH, segment of one of these cases showed intraclonal sequence heterogeneity, indicating ongoing somatic mutation. In five cases, the distribution and type of mutations indicated that tumor cells had been selected by antigen. Because somatically mutated Ig genes are expressed by B cells that have reached a germinal center/post-germinal center stage of development, these findings suggest that the PEL cell of origin is a germinal center or post-germinal center B cell in most cases. In contrast, the VH gene segment expressed by tumor cells of the BC-3 cell line, which was originated from an EBV-negative PEL obtained from an HIV-negative patient, was unmutated, suggesting a pre-germinal center B cell origin for tumor cells of this particular PEL cell line. Taken together, these findings suggest that development of PELs may not be restricted to one stage of B cell differentiation and may represent transformation of B cells at different stages of ontogeny.

Amino Acid Sequence↗
PubMed1997

Kaposi's sarcoma-associated herpesvirus sequences in benign lymphoid proliferations not associated with human immunodeficiency virus.

BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV) DNA sequences have been identified in approximately 95% of Kaposi's sarcoma (KS) lesions and primary effusion lymphomas (PELs), suggesting a pathogenetic role for this virus in these lesions. However, KSHV has also been identified in a variety of specimens, including lymph nodes, peripheral blood B cells, semen, and prostate tissue, with varying frequencies. This suggests that KSHV, like Epstein-Barr virus, may be ubiquitously distributed. To evaluate further the clinical spectrum of KSHV infection and define better the prevalence of this virus in lymphoid tissues in the general population, the authors examined a wide spectrum of benign lymphoid proliferations occurring in human immunodeficiency virus (HIV)-negative individuals. METHODS: One hundred eight lymphoid lesions were examined for the presence of KSHV by polymerase chain reaction (PCR) amplification using primers to open reading frame (ORF) 26. Positive cases were confirmed by Southern blot hybridization using an internal oligonucleotide probe and by PCR amplification using primers to ORF 74 and ORF 75 of the virus. RESULTS: Only 4 (4%) of 108 specimens were KSHV positive. Three positive lymph node specimens were taken from patients with multicentric Castleman's disease (3 of 11 total cases of Castleman's disease; 3 of 5 total cases of multicentric Castleman's disease). The remaining case was a lymph node showing paracortical hyperplasia, taken from a patient with systemic lupus erythematosus. CONCLUSIONS: KSHV is not detectable by PCR technology in a wide range of lymphoid proliferations occurring outside of HIV infection. These studies further support the contention that KSHV is preferentially associated with KS, PEL, and some cases of multicentric Castleman's disease.

Adolescent↗
PubMed1997

Epstein-Barr virus latent gene expression in primary effusion lymphomas containing Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8.

Primary effusion (body cavity-based) lymphoma (PEL) is a recently recognized subtype of malignant lymphoma that exhibits distinctive clinical and biological features, most notably its usual infection with the Kaposi's sarcoma-associated herpesvirus (KSHV). The vast majority of cases also contain Epstein-Barr virus (EBV). This dual viral infection is the first example of a consistent dual herpesviral infection in a human neoplasm and provides a unique model to study viral interactions. We analyzed the pattern of EBV latent gene expression to determine the pathogenic role of this agent in PELs. We examined five PELs coinfected with EBV and KSHV by reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry. EBER1 mRNA, a consistent marker of viral latency, was positive in all PEL cases, although at lower levels than in the non-PEL controls due to EBER1 expression by only a variable subset of lymphoma cells. Qp-initiated mRNA, encoding only EBNA1 and characteristic of latencies I and II, was positive in all PEL cases. Wp- and Cp-initiated mRNAs, encoding all EBNAs and characteristic of latency III, were negative in all cases. LMP1 mRNA, expressed in latencies II and III, was present in three cases of PEL, although at very low levels that were not detectable at the protein level by immunohistochemistry. Low levels of LMP2A mRNA were detected in all cases. BZLF1, an early-intermediate lytic phase marker, was weakly positive in four cases, suggesting a productive viral infection in a very small proportion of cells, which was confirmed by ZEBRA antigen expression. Therefore, PELs exhibit a restricted latency pattern, with expression of EBNA1 in all cases, and low LMP1 and LMP2A levels.

Adult↗
PubMed1997

Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation.

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.

Animals↗
PubMed1997

Kaposi's sarcoma-associated herpesvirus and human herpesvirus 8 (KSHV/HHV8)-associated lymphoma of the bowel. Report of two cases in HIV-positive men with secondary effusion lymphomas.

This report describes two cases of Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/HHV8)-associated lymphomas that primarily involved the large bowel and that secondarily caused malignant effusions. Involvement of the gastrointestinal tract is of interest because epidemiologic evidence suggests that KSHV/HHV-8 may be transmitted via the fecal-oral route, and KSHV/HHV8 DNA has been detected in rectal samples from HIV-positive patients. This report describes two HIV-positive men who developed primary KSHV/ HHV8-associated lymphomas of the bowel. Despite similar morphology and immunophenotype, these cases differ from most KSHV/HHV8-associated primary effusion lymphomas, which present with malignant effusions in the absence of a solid tumor mass. The spectrum of KSHV/HHV8-associated lymphomas is expanded to include a subset of primary bowel lymphomas in individuals infected with human immunodeficiency virus.

AIDS-Related Opportunistic Infections↗
PubMed1997

Cyclin D1 and retinoblastoma protein expression in Kaposi's sarcoma.

Cyclins are implicated in the induction and control of the cell cycle. Cyclin D1 regulates G1-phase progression by phosphorylation of the retinoblastoma protein (pRb). The Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV) contains and transcribes an open reading frame with sequence similarities to cellular D-type cyclins. The KSHV-cyclin protein is associated with kinase activity capable of phosphorylating pRb in vitro. Here, we study for the first time the endogenous cyclin D1 and Rb protein expression in Kaposi's sarcoma (KS) tissue. Twenty-four consecutive biopsies of AIDS-related (n=21) and classical (n=3) KS were studied by immunohistochemistry with monoclonal antibodies against cyclin D1 and pRb. We detected cyclin D1 in 1 of 13 patch/plaque stage, in 4 of 5 nodular stage and in 3 of 6 visceral KS lesions. By Western blot analysis, this cellular cyclin D1 monoclonal antibody did not cross-react with the purified KSHV-cyclin protein. The pRb was consistently detected in 24 of 24 KS lesions. In summary, early KS lesions rarely have detectable expression of endogenous cyclin D1. Advanced and disseminated KS lesions tend to have overexpression of endogenous cyclin D1. Therefore, cellular cyclin D1 expression appears to correlate with tumor progression in KS. The endogenous cyclin D1 is antigenically distinct from the KSHV-cyclin homolog. The pRb, which may serve as a substrate for KSHV-cyclin, is found in all KS lesions examined.

Antibodies, Monoclonal↗
PubMed1997

Molecular pathology of posttransplantation lymphoproliferative disorders.

Posttransplantation lymphoproliferative disorders (PT-LPDs) represent a heterogeneous group of Epstein-Barr virus (EBV) associated lymphoid proliferations occurring in the setting of immunosuppression associated with solid organ transplantation. Some PT-LPDs regress after a reduction in immunosuppression, whereas others progress despite aggressive therapy. Previously defined histopathologic categories do not correlate with clonality, and neither histopathology nor clonality has reliably predicted their clinical behavior. Recently, correlative clinical, morphological, and molecular genetic analysis has suggested that PT-LPDs are divisible into three distinct clinically relevant categories as follows: (1) plasmacytic hyperplasia: most commonly arise in the oropharynx or lymph nodes, are nearly always polyclonal, usually contain multiple EBV infectious events or only a minor cell population infected by a single form of EBV, and lack oncogene or tumor suppressor gene alterations; (2) polymorphic lymphoproliferative disorders: may arise in lymph nodes or extranodal sites including the gastrointestinal tract and lungs, are nearly always monoclonal based on the presence of clonal immunoglobulin gene rearrangements, usually contain a single form of EBV, and lack oncogene or tumor suppressor gene alterations; and (3) malignant lymphoma or multiple myeloma: present with widely disseminated disease frequently including the bone marrow, are monoclonal based on clonal immunoglobulin gene rearrangements, contain a single form of EBV, and contain alterations of one or more oncogenes or tumor suppressor genes (c-myc, ras, p53). Thus, proto-oncogene and tumor suppressor gene alterations appear to be associated with disease progression and an often fatal clinical outcome. Furthermore, multiple PT-LPD lesions occurring in the same individual but in multiple anatomic sites, either simultaneously or dysynchronously over time, may show distinct clonal immunoglobulin gene rearrangement patterns and evidence of infection by different forms of EBV, suggesting that each lesion represents a distinct clonal neoplasm that may show distinctive clinical behavior. Therefore, whenever possible, a biopsy of each one of the several PT-LPD lesions occurring in an individual should be obtained to derive a true assessment of the pathobiological nature and clinical aggressiveness of an individual's disease.

Herpesviridae Infections↗
PubMed1997

Kaposi's sarcoma-associated herpesvirus: a lymphotropic human herpesvirus associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease.

Despite extensive epidemiological evidence suggesting that Kaposi's sarcoma (KS) has an infectious origin, a specific viral association with KS had not been documented until recently, when two novel DNA fragments were identified in KS lesional tissue from a patient with the acquired immunodeficiency syndrome (AIDS). These fragments belong to a previously unidentified human herpesvirus, called KS-associated herpesvirus (KSHV), or human herpesvirus 8. Although this virus is generally absent from normal control tissues, inflammatory conditions, and a variety of tumors, it is present in most AIDS- as well as non-AIDS-related KS lesions, suggesting that it is not simply an opportunistic infection in human immunodeficiency virus (HIV)-infected patients. Furthermore, this virus is consistently present in a specific type of non-Hodgkin's lymphoma, frequently although not exclusively occurring in patients with AIDS (namely, the primary effusion lymphomas, previously called body cavity-based lymphomas). KSHV is also present in a significant proportion of cases of AIDS- and non-AIDS-related multicentric Castleman's disease. Sequence analysis has led to the identification of genes in the KSHV genome that may have important pathobiological functions, and experimental approaches have been developed to isolate, grow and transmit KSHV in vitro. An understanding of KSHV is important for evaluating its role in the pathogenesis of Kaposi's sarcoma, primary effusion lymphomas, and multicentric Castleman's disease, and to help develop better methods for the prevention and treatment of these diseases.

Castleman Disease↗
PubMed1997

The Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) in Kaposi's sarcoma, malignant lymphoma, and other diseases.

BACKGROUND: Two novel nonhuman DNA fragments were discovered in an AIDS-related Kaposi's sarcoma (KS) lesion using representational difference analysis. DESIGN: These sequences belong to a previously unidentified gamma-2-herpesvirus exhibiting homology with Herpesvirus saimiri and Epstein-Barr virus. This virus was named Kaposi's sarcoma-associated herpesvirus (KSHV) and provisionally designated human herpesvirus-8 (HHV-8). RESULTS: KSHV is detectable in more than 90% of classical-Mediterranean, iatrogenic, endemic-African, and AIDS-epidemic KS lesions. In situ PCR studies have demonstrated KSHV in the spindle cells and endothelial cells of KS lesions. KSHV appears to be a transmissible B-lymphotropic herpesvirus. It is detectable in circulating B cells in some HIV-infected patients, and this finding appears to predict the future development of KS among these individuals. KSHV has been identified in a rare and distinct subset of malignant lymphoma referred to as body cavity-based lymphoma but not in other lymphoid neoplasms. KSHV is absent from most other HIV- and non-HIV-associated lymphadenopathies. CONCLUSIONS: Further studies should lead to a better understanding of the role of KSHV in the pathogenesis of these disorders and may eventually show that KSHV represents the long sought-after etiologic agent of Kaposi's sarcoma.

Herpesvirus 8, Human↗
PubMed1997

Epstein-Barr virus latent membrane protein-1 oncogene deletion in post-transplantation lymphoproliferative disorders.

Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is a multifunctional oncoprotein. A 30-bp deletion of the 3' end of the LMP1 gene (del-LMP1) has been identified in some EBV isolates. This deleted LMP1 gene encodes a protein, altered on the carboxy terminus, which is thought to have greater oncogenic potential than the wild type. Recently, it was suggested that del-LMP1 plays a role in the development of malignant lymphomas occurring in immunocompromised patients. To further elucidate the role of del-LMP1 in post-transplantation lymphoproliferative disorders (PT-LPDs) we analyzed 58 PT-LPD lesions from 36 heart and kidney organ transplant recipients. Overall, del-LMP1 was detected in 44% of the cases. Four plasmacytic hyperplasias (36%), eight polymorphic B-cell hyperplasias/polymorphic B-cell lymphomas (38%), and five malignant lymphomas/multiple myelomas (71%) exhibited del-LMP1. Two of the three patients displaying disease progression showed wild-type LMP1 gene (w-LMP1) and one showed del-LMP1. LMP1 status remained the same in all three patients during disease progression. In patients undergoing biopsy of multiple separate PT-LPD lesions representing different clonal lymphoid proliferations, LMP1 status was the same in all of the lesions in each patient. Furthermore, although the polyclonal lesions harbor multiple EBV infectious events, they either showed w- or del-LMP1 but not both. Analysis of the tissues without an apparent PT-LPD (peripheral blood, bone marrow, or colon) revealed EBV and LMP1 type identical to that found in the lesions. In conclusion, the presence or absence of del-LMP1 in PT-LPDs does not correlate with the histopathological category or the malignant nature of the lymphoid proliferation. LMP1 status does not change during disease progression and is the same within multiple lesions occurring in the same patient regardless of their clonal relationship. These findings suggest that 1) EBV infection in patients with PT-LPDs occurs with a w- or del-LMP1-type EBV isolate and does not change once a patient acquires the virus and 2) the infection is an early event in the development of PT-LPDs and transformation is induced regardless of the type of LMP1.

Adolescent↗
PubMed1996

Primary effusion lymphoma in women: report of two cases of Kaposi's sarcoma herpes virus-associated effusion-based lymphoma in human immunodeficiency virus-negative women.

Recent molecular evidence suggests an association with a new herpes virus, Kaposi's sarcoma-associated herpes virus (KSHV/HHV-8), and primary effusion lymphomas (PEL). PELs have a characteristic morphology, phenotype, and clinical presentation with malignant effusions in the absence of a contiguous solid tumor mass. Most cases of PEL have occurred in human immunodeficiency virus (HIV)-positive male patients who are coinfected with Epstein-Barr virus (EBV). This report describes two cases of PEL in HIV- and EBV-negative women. In one patient, a pleural cavity PEL was preceded by classic Kaposi's Sarcoma (KS) of the lower extremities. In the second patient, PEL developed in an artificial cavity related to the capsule of a breast implant. Both cases had the characteristic morphologic appearance of high-grade anaplastic/B-cell immunoblastic lymphomas, with loss of B-cell differentiation antigens, clonal immunoglobulin heavy chain gene rearrangements, and expression of activation antigen CD30. Both cases were negative for EBV, herpes virus simplex, and cytomegalovirus (CMV). DNA extracted from both lymphomas and skin KS specimen showed KSHV sequences by molecular analysis. This report expands the spectrum of KSHV-associated disease to include PEL in HIV-negative women.

Aged↗