scholarly journals Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. e32-e39 ◽  
Author(s):  
Debasmita Roy ◽  
Sang-Hoon Sin ◽  
Blossom Damania ◽  
Dirk P. Dittmer
Keyword(s):  
Fragile Site ◽  
Primary Effusion Lymphoma ◽  
Snp Array ◽  
Kaposi Sarcoma ◽  
B Cell Lymphoma ◽  
Host Chromosome ◽  
Barr Virus ◽  
Genomic Aberrations ◽  
Host Genetic ◽  
Epstein Barr

Abstract Primary effusion lymphoma (PEL) is a diffuse-large B-cell lymphoma with poor prognosis. One hundred percent of PELs carry the genome of Kaposi sarcoma–associated herpesvirus and a majority are coinfected with Epstein-Barr virus (EBV). We profiled genomic aberrations in PEL cells using the Affymetrix 6.0 SNP array. This identified for the first time individual genes that are altered in PEL cells. Eleven of 13 samples (85%) were deleted for the fragile site tumor suppressors WWOX and FHIT. Alterations were also observed in the DERL1, ETV1, RASA4, TPK1, TRIM56, and VPS41 genes, which are yet to be characterized for their roles in cancer. Coinfection with EBV was associated with significantly fewer gross genomic aberrations, and PEL could be segregated into EBV-positive and EBV-negative clusters on the basis of host chromosome alterations. This suggests a model in which both host genetic aberrations and the 2 viruses contribute to the PEL phenotype.

scholarly journals Epstein–Barr virus enhances genome maintenance of Kaposi sarcoma-associated herpesvirus

2018 ◽  
Vol 115 (48) ◽  
pp. E11379-E11387 ◽  
Author(s):  
Rachele Bigi ◽  
Justin T. Landis ◽  
Hyowon An ◽  
Carolina Caro-Vegas ◽  
Nancy Raab-Traub ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Primary Effusion Lymphoma ◽  
Kaposi Sarcoma ◽  
B Cell Lymphoma ◽  
Nuclear Antigen ◽  
Genome Maintenance ◽  
Barr Virus ◽  
Single Positive ◽  
Infected Cells ◽  
Epstein Barr

Primary effusion lymphoma (PEL) is a B cell lymphoma that is always associated with Kaposi’s sarcoma-associated herpesvirus (KSHV) and in many cases also with Epstein–Barr virus (EBV); however, the requirement for EBV coinfection is not clear. Here, we demonstrate that adding exogenous EBV to KSHV+single-positive PEL leads to increased KSHV genome maintenance and KSHV latency-associated nuclear antigen (LANA) expression. To show that EBV was necessary for naturally coinfected PEL, we nucleofected KSHV+/EBV+PEL cell lines with an EBV-specific CRISPR/Cas9 plasmid to delete EBV and observed a dramatic decrease in cell viability, KSHV genome copy number, and LANA expression. This phenotype was reversed by expressing Epstein–Barr nuclear antigen 1 (EBNA-1)in trans, even though EBNA-1 and LANA do not colocalize in infected cells. This work reveals that EBV EBNA-1 plays an essential role in the pathogenesis of PEL by increasing KSHV viral load and LANA expression.

Inhibition of NF-κB induces apoptosis of KSHV-infected primary effusion lymphoma cells

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2537-2542 ◽  
Author(s):  
Shannon A. Keller ◽  
Elaine J. Schattner ◽  
Ethel Cesarman
Keyword(s):  
Primary Effusion Lymphoma ◽  
Leukemia Virus ◽  
Human Lymphocytes ◽  
Kaposi Sarcoma ◽  
Irreversible Inhibitor ◽  
Mobility Shift ◽  
Lymphoma Cells ◽  
Barr Virus ◽  
Human T Cell ◽  
Epstein Barr

Abstract Kaposi sarcoma–associated herpesvirus (KSHV), or human herpervirus 8 (HHV-8), is a γ-herpesvirus that infects human lymphocytes and is associated with primary effusion lymphoma (PEL). Currently, the role of viral infection in the transformation of PEL cells is unknown. One possibility is that KSHV, like the lymphotropic viruses Epstein-Barr virus (EBV) and human T-cell leukemia virus I (HTLV-I), activates the transcription factor NF-κB to promote survival and proliferation of infected lymphocytes. To examine this possibility, we assessed NF-κB activity in KSHV-infected PEL cell lines and primary tumor specimens by electrophoretic mobility shift assay (EMSA). We observed that NF-κB is constitutively activated in all KSHV-infected lymphomas, and consists of 2 predominant complexes, p65/p50 heterodimers and p50/p50 homodimers. Inhibition experiments demonstrated that Bay 11-7082, an irreversible inhibitor of IκBα phosphorylation, completely and specifically abrogated the NF-κB/DNA binding in PEL cells. PEL cells treated with Bay 11 demonstrated down-regulation of the NF-κB inducible cytokine interleukin 6 (IL-6), and apoptosis. These results suggest that NF-κB activity is necessary for survival of KSHV-infected lymphoma cells, and that pharmacologic inhibition of NF-κB may be an effective treatment for PEL.

scholarly journals Impact of Myc in HIV-associated non-Hodgkin lymphomas treated with EPOCH and outcomes with vorinostat (AMC-075 trial)

Blood ◽  
2020 ◽  
Vol 136 (11) ◽  
pp. 1284-1297 ◽  
Author(s):  
Juan C. Ramos ◽  
Joseph A. Sparano ◽  
Amy Chadburn ◽  
Erin G. Reid ◽  
Richard F. Ambinder ◽  
...  
Keyword(s):  
B Cell ◽  
Negative Impact ◽  
Primary Effusion Lymphoma ◽  
Human Herpesvirus ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Hiv Reservoirs ◽  
Herpesvirus Type ◽  
Barr Virus ◽  
Epstein Barr

Abstract EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384.

Hematological cancers in individuals infected by HIV

Blood ◽  
2021 ◽  
Author(s):  
Antonino Carbone ◽  
Emanuela Vaccher ◽  
Annunziata Gloghini
Keyword(s):  
Kaposi Sarcoma ◽  
B Cell Lymphoma ◽  
Castleman Disease ◽  
International Agency ◽  
Term Survival ◽  
Multicentric Castleman Disease ◽  
Barr Virus ◽  
Hematological Cancers ◽  
Epstein Barr ◽  
Cytokine Dysregulation

HIV infection increases cancer risk and is linked to cancers associated to infectious agents classified as carcinogenic to humans by the International Agency for Research on Cancer. Lymphomas represent one of the most frequent malignancies among individuals infected by HIV. Diffuse large B-cell lymphoma remains a leading cancer after the introduction of combined antiretroviral therapy (cART). The incidence of other lymphomas including Burkitt lymphoma, primary effusion lymphomas, and plasmablastic lymphoma of the oral cavity remain stable, while the incidence of Hodgkin lymphoma and Kaposi sarcoma-associated herpesvirus (KSHV)-associated Multicentric Castleman Disease has increased. The heterogeneity of lymphomas in individuals infected by HIV likely depends on the complexity of involved pathogenetic mechanisms, i.e. HIV-induced immunosuppression, genetic abnormalities, cytokine dysregulation, co-infection with the gamma-herpesviruses, Epstein Barr virus and KSHV, and the dysregulation of the immune responses controlling these viruses. In the modern cART era, standard treatments for HIV-associated lymphoma including stem cell transplantation in relapsed/refractory disease, mirrors that of the general population. The combination of cART and anti neoplastic treatments has resulted in remarkable prolongation of long-term survival. However, oncolytic and immunotherapic strategies, and therapies targeting specific viral oncogenes will need to be developed primarily.

The viral interferon-regulatory factor-3 is required for the survival of KSHV-infected primary effusion lymphoma cells

Blood ◽  
2008 ◽  
Vol 111 (1) ◽  
pp. 320-327 ◽  
Author(s):  
Effi Wies ◽  
Yasuko Mori ◽  
Alexander Hahn ◽  
Elisabeth Kremmer ◽  
Michael Stürzl ◽  
...  
Keyword(s):  
Primary Effusion Lymphoma ◽  
Human Herpesvirus ◽  
Kaposi Sarcoma ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Knock Down ◽  
Barr Virus ◽  
Caspase 7 ◽  
Epstein Barr

Human herpesvirus-8 (HHV-8), also known as Kaposi sarcoma–associated herpesvirus (KSHV), is etiologically linked to primary effusion lymphoma (PEL). At least 10 KSHV-encoded proteins with potential roles in KSHV-associated neoplasia have been identified. However, with few exceptions, these putative oncogenes were analyzed in heterologous systems only using overexpression of single genes. Thus, the pathogenetic relevance of most of these putative oncogenes remains essentially unclear. We used RNA interference (RNAi) to knock down the expression of several KSHV genes in cultured PEL cells carrying the KSHV genome. The viral interferon-regulatory factor-3 (vIRF-3) was found to be required for proliferation and survival of cultured PEL cells. Knock-down of vIRF-3 expression by various RNAi approaches unequivocally resulted in reduced proliferation and increased activity of caspase-3 and/or caspase-7. Thus, vIRF-3 can be seen as a bona fide oncogene of KSHV-associated lymphoma. Surprisingly, although the related Epstein-Barr virus (EBV) is usually sufficient to immortalize human B lymphocytes, silencing of vIRF-3 reduced the viability of both EBV− and EBV+ PEL cells. This suggests that KSHV is the driving force in the pathogenesis of PEL.

scholarly journals Widespread Traces of Lytic Kaposi Sarcoma-Associated Herpesvirus in Primary Effusion Lymphoma at Single-Cell Resolution

2020 ◽  
Vol 9 (45) ◽  
Author(s):  
Nicole C. Rondeau ◽  
Michael O. Finlayson ◽  
JJ L. Miranda
Keyword(s):  
Single Cell ◽  
Epstein Barr Virus ◽  
Primary Effusion Lymphoma ◽  
Kaposi Sarcoma ◽  
Cell Culture Model ◽  
Barr Virus ◽  
Culture Model ◽  
Single Cell Rna Sequencing ◽  
A Cell ◽  
Epstein Barr

ABSTRACT Cancer cells of primary effusion lymphoma (PEL) often contain both Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). We measured the interplay of human, KSHV, and EBV transcription in a cell culture model of PEL using single-cell RNA sequencing. The data detect widespread trace expression of lytic KSHV genes.

scholarly journals Lymphotropic Viruses EBV, KSHV and HTLV in Latin America: Epidemiology and Associated Malignancies. A Literature-Based Study by the RIAL-CYTED

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2166
Author(s):  
Paola Chabay ◽  
Daniela Lens ◽  
Rocio Hassan ◽  
Socorro María Rodríguez Pinilla ◽  
Fabiola Valvert Gamboa ◽  
...  
Keyword(s):  
Latin America ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Kaposi Sarcoma ◽  
B Cell Lymphoma ◽  
Close Correlation ◽  
Developed Countries ◽  
Barr Virus ◽  
The North ◽  
Epstein Barr

The Epstein–Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) and human T-lymphotropic virus (HTLV-1) are lymphomagenic viruses with region-specific induced morbidity. The RIAL-CYTED aims to increase the knowledge of lymphoma in Latin America (LA), and, as such, we systematically analyzed the literature to better understand our risk for virus-induced lymphoma. We observed that high endemicity regions for certain lymphomas, e.g., Mexico and Peru, have a high incidence of EBV-positive lymphomas of T/NK cell origin. Peru also carries the highest frequency of EBV-positive classical Hodgkin lymphoma (HL) and EBV-positive diffuse large B cell lymphoma, not otherwise specified (NOS), than any other LA country. Adult T cell lymphoma is endemic to the North of Brazil and Chile. While only few cases of KSHV-positive lymphomas were found, in spite of the close correlation of Kaposi sarcoma and the prevalence of pathogenic types of KSHV. Both EBV-associated HL and Burkitt lymphoma mainly affect young children, unlike in developed countries, in which adolescents and young adults are the most affected, correlating with an early EBV seroconversion for LA population despite of lack of infectious mononucleosis symptoms. High endemicity of KSHV and HTLV infection was observed among Amerindian populations, with differences between Amazonian and Andean populations.

Inhibition of NF-κB induces apoptosis of KSHV-infected primary effusion lymphoma cells

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2537-2542 ◽  
Author(s):  
Shannon A. Keller ◽  
Elaine J. Schattner ◽  
Ethel Cesarman
Keyword(s):  
Primary Effusion Lymphoma ◽  
Leukemia Virus ◽  
Human Lymphocytes ◽  
Kaposi Sarcoma ◽  
Irreversible Inhibitor ◽  
Mobility Shift ◽  
Lymphoma Cells ◽  
Barr Virus ◽  
Human T Cell ◽  
Epstein Barr

Kaposi sarcoma–associated herpesvirus (KSHV), or human herpervirus 8 (HHV-8), is a γ-herpesvirus that infects human lymphocytes and is associated with primary effusion lymphoma (PEL). Currently, the role of viral infection in the transformation of PEL cells is unknown. One possibility is that KSHV, like the lymphotropic viruses Epstein-Barr virus (EBV) and human T-cell leukemia virus I (HTLV-I), activates the transcription factor NF-κB to promote survival and proliferation of infected lymphocytes. To examine this possibility, we assessed NF-κB activity in KSHV-infected PEL cell lines and primary tumor specimens by electrophoretic mobility shift assay (EMSA). We observed that NF-κB is constitutively activated in all KSHV-infected lymphomas, and consists of 2 predominant complexes, p65/p50 heterodimers and p50/p50 homodimers. Inhibition experiments demonstrated that Bay 11-7082, an irreversible inhibitor of IκBα phosphorylation, completely and specifically abrogated the NF-κB/DNA binding in PEL cells. PEL cells treated with Bay 11 demonstrated down-regulation of the NF-κB inducible cytokine interleukin 6 (IL-6), and apoptosis. These results suggest that NF-κB activity is necessary for survival of KSHV-infected lymphoma cells, and that pharmacologic inhibition of NF-κB may be an effective treatment for PEL.

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