RESUMO
Primary effusion lymphoma (PEL) is a malignant B-cell lymphoma attributable to Kaposi sarcoma-associated herpesvirus (KSHV) infection. PEL is characterized by invasive behavior, showing recurrent effusions in body cavities. The clinical outcome and typical prognosis in patients with PEL are poor and potentially lethal. Clarification of the pathogenesis in PEL is urgently needed in order to develop novel therapies. PEL cells generally lack B-cell surface markers, and we therefore hypothesized that the B-cell transcription factor, PAX5, would be down-regulated in PEL. The expression of PAX5 is detected from the pro-B to the mature B-cell stage and is indispensable for the differentiation of B-cells. PAX5 was silenced in PEL cells via its promoter methylation. Up-regulation of PAX5 induced several genes coding for B-cell surface marker mRNA, but not protein level. PAX5 inhibited cell growth via G1 cell cycle arrest. PAX5 bound to RB and increased its protein expression. RB/E2F-regulated genes were significantly down-regulated in microarray analysis and PCR experiments. To elucidate the in vivo role of PAX5, we examined the restoration of PAX5 in a PEL mouse model. The ascites volume and organ invasions were significantly suppressed by PAX5 restoration. Reduction of PAX5 has played a crucial role in the oncogenesis of PEL, and PAX5 is a tumor suppressor in PEL. Targeting PAX5 could represent a novel therapeutic strategy for patients with PEL.
Assuntos
Pontos de Checagem do Ciclo Celular , Herpesvirus Humano 8 , Linfoma de Efusão Primária , Fator de Transcrição PAX5 , Fator de Transcrição PAX5/metabolismo , Fator de Transcrição PAX5/genética , Linfoma de Efusão Primária/virologia , Linfoma de Efusão Primária/metabolismo , Linfoma de Efusão Primária/genética , Linfoma de Efusão Primária/patologia , Linfoma de Efusão Primária/etiologia , Animais , Humanos , Herpesvirus Humano 8/genética , Camundongos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Proliferação de Células , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/virologia , Regiões Promotoras Genéticas , Modelos Animais de DoençasRESUMO
Primary effusion lymphoma (PEL) is a rare B-cell non-Hodgkin lymphoma associated with Kaposi Sarcoma-associated herpesvirus (KSHV/HHV8) infection. Lymphoma cells are coinfected with Epstein-Barr virus (EBV) in 60-80% of cases. Tools allowing a reliable PEL diagnosis are lacking. This study reports PEL diagnosis in 4 patients using a Flow-Fluorescence in situ hybridization (FlowFISH) technique that allowed detection of differentially expressed EBV and HHV8 transcripts within the same sample, revealing viral heterogeneity of the disease. Moreover, infected cells exhibited variable expressions of CD19, CD38, CD40, and CD138. Therefore, FlowFISH is a promising tool to diagnose and characterize complex viral lymphoproliferations.
Assuntos
Herpesvirus Humano 4 , Herpesvirus Humano 8 , Hibridização in Situ Fluorescente , Linfoma de Efusão Primária , Humanos , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/isolamento & purificação , Hibridização in Situ Fluorescente/métodos , Linfoma de Efusão Primária/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Masculino , Idoso , Pessoa de Meia-Idade , Feminino , Infecções por Herpesviridae/virologia , Infecções por Herpesviridae/diagnóstico , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Idoso de 80 Anos ou maisRESUMO
Primary effusion lymphoma (PEL) is an uncommon B-cell lymphoma associated with human herpesvirus 8 and comprises 3-4% of all HIV-related lymphomas. It traditionally presents as a pleural, pericardial, and/or peritoneal effusion, though it can occasionally manifest as an extracavitary or solid mass in the absence of an effusion. The extracavitary or solid variant of primary effusion lymphoma has been reported in the skin, gastrointestinal tract, lung, and lymph nodes. However, very few cases have been reported in the central nervous system. We describe a case of extracavitary or solid variant of primary effusion lymphoma presenting as a brain mass in an HIV-positive man, highlighting the clinicopathologic and immunophenotypic findings of a rare entity.
Primary effusion lymphoma (PEL) is an uncommon and aggressive form of large B-cell lymphoma with a grim outlook, making up less than 1% of all lymphomas. PEL is linked to human herpesvirus 8 and predominantly impacts individuals with HIV or weakened immune systems. The typical presentation of PEL involves cancerous fluid accumulating in the chest or abdominal cavities. Occasionally, PEL can appear as a solid mass outside these cavities, termed extracavitary PEL (EC-PEL). The case we are describing highlights the difficulties in diagnosing PEL/EC-PEL. It is crucial for healthcare providers to consider EC-PEL when dealing with human herpesvirus 8-positive B-cell lymphomas, especially when patients have weakened immune systems and an unusual clinical scenario involving a solid mass, as seen in this case.
Assuntos
Neoplasias Encefálicas , Linfoma de Efusão Primária , Humanos , Linfoma de Efusão Primária/patologia , Linfoma de Efusão Primária/diagnóstico , Masculino , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico , Pessoa de Meia-IdadeRESUMO
Kaposi sarcoma associated herpesvirus (KSHV) is associated with around 1% of all human tumors, including the B cell malignancy primary effusion lymphoma (PEL), in which co-infection with the Epstein Barr virus (EBV) can almost always be found in malignant cells. Here, we demonstrate that KSHV/EBV co-infection of mice with reconstituted human immune systems (humanized mice) leads to IgM responses against both latent and lytic KSHV antigens, and expansion of central and effector memory CD4+ and CD8+ T cells. Among these, KSHV/EBV dual-infection allows for the priming of CD8+ T cells that are specific for the lytic KSHV antigen K6 and able to kill KSHV/EBV infected B cells. This suggests that K6 may represent a vaccine antigen for the control of KSHV and its associated pathologies in high seroprevalence regions, such as Sub-Saharan Africa.
Assuntos
Linfócitos B , Linfócitos T CD8-Positivos , Herpesvirus Humano 8 , Animais , Herpesvirus Humano 8/imunologia , Humanos , Linfócitos B/imunologia , Camundongos , Linfócitos T CD8-Positivos/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Coinfecção/imunologia , Coinfecção/virologia , Linfócitos T CD4-Positivos/imunologia , Herpesvirus Humano 4/imunologia , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Imunoglobulina M/imunologia , Antígenos Virais/imunologia , Camundongos SCID , Linfoma de Efusão Primária/imunologia , Linfoma de Efusão Primária/virologia , Anticorpos Antivirais/imunologiaRESUMO
TRIM32 is often aberrantly expressed in many types of cancers. Kaposi's sarcoma-associated herpesvirus (KSHV) is linked with several human malignancies, including Kaposi's sarcoma and primary effusion lymphomas (PELs). Increasing evidence has demonstrated the crucial role of KSHV lytic replication in viral tumorigenesis. However, the role of TRIM32 in herpesvirus lytic replication remains unclear. Here, we reveal that the expression of TRIM32 is upregulated by KSHV in latency, and reactivation of KSHV lytic replication leads to the inhibition of TRIM32 in PEL cells. Strikingly, RTA, the master regulator of lytic replication, interacts with TRIM32 and dramatically promotes TRIM32 for degradation via the proteasome systems. Inhibition of TRIM32 induces cell apoptosis and in turn inhibits the proliferation and colony formation of KSHV-infected PEL cells and facilitates the reactivation of KSHV lytic replication and virion production. Thus, our data imply that the degradation of TRIM32 is vital for the lytic activation of KSHV and is a potential therapeutic target for KSHV-associated cancers. IMPORTANCE: TRIM32 is associated with many cancers and viral infections; however, the role of TRIM32 in viral oncogenesis remains largely unknown. In this study, we found that the expression of TRIM32 is elevated by Kaposi's sarcoma-associated herpesvirus (KSHV) in latency, and RTA (the master regulator of lytic replication) induces TRIM32 for proteasome degradation upon viral lytic reactivation. This finding provides a potential therapeutic target for KSHV-associated cancers.
Assuntos
Herpesvirus Humano 8 , Proteínas Imediatamente Precoces , Proteólise , Transativadores , Fatores de Transcrição , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Ativação Viral , Replicação Viral , Humanos , Apoptose , Linhagem Celular , Herpesvirus Humano 8/crescimento & desenvolvimento , Herpesvirus Humano 8/metabolismo , Herpesvirus Humano 8/patogenicidade , Herpesvirus Humano 8/fisiologia , Proteínas Imediatamente Precoces/metabolismo , Proteínas Imediatamente Precoces/genética , Linfoma de Efusão Primária/virologia , Linfoma de Efusão Primária/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Sarcoma de Kaposi/virologia , Sarcoma de Kaposi/metabolismo , Transativadores/metabolismo , Transativadores/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Latência ViralRESUMO
A 67-year-old man underwent renal transplantation in his twenties. He developed refractory pleural effusion, with many large lymphocytes with severe atypia and mitosis in the effusion, indicating malignant lymphoma. He finally died of respiratory failure. An autopsy revealed atypical lymphocytes positive for CD3, CD4, and CD30 and negative for CD8, CD20, PAX5, human herpesvirus (HHV) 8, and Epstein-Barr virus-encoded small RNAs by immunohistochemistry and in situ hybridization. Atypical lymphocytes also had T-cell receptor gene rearrangements Jß2, Jγ2, and Jδ1 and chromosomal aberrations der(8)t(1;8)(q21;p21), add(13)(q12), add(14)(q32), and add(16)(q12-13). A few atypical lymphocytes were present at other sites. We finally diagnosed this case as monomorphic T-cell post-transplant lymphoproliferative disorder with features of HHV8-negative primary effusion lymphoma. A literature review only identified six cases (four HHV8-negative, two HHV8-positive) of effusion lymphoma of T-cell type, including the present case. Interestingly, about half of HHV8-negative and HHV8-positive cases had a history of renal transplantation in their twenties. All cases showed tumor CD30 expression, whereas CD4 and CD8 expressions were inconsistent. These findings indicated that this lymphoma may be associated with post-transplant lymphoproliferative disorder by renal transplantation at a young age, although further cases need to be analyzed.
Assuntos
Autopsia , Herpesvirus Humano 8 , Transplante de Rim , Linfoma de Efusão Primária , Humanos , Masculino , Idoso , Linfoma de Efusão Primária/patologia , Linfoma de Efusão Primária/virologia , Transplante de Rim/efeitos adversos , Herpesvirus Humano 8/isolamento & purificação , Herpesvirus Humano 8/genética , Linfócitos T/imunologia , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/virologia , Transtornos Linfoproliferativos/etiologia , Evolução FatalRESUMO
Non-Hodgkin lymphoma (NHL) is a common cancer in both men and women and represents a significant cancer burden worldwide. Primary effusion lymphoma (PEL) is a subtype of NHL infected with Kaposi sarcoma-associated herpesvirus (KSHV). PEL is an aggressive and lethal cancer with no current standard of care, owing largely to its propensity to develop resistance to current chemotherapeutic regimens. Here, we report a reliance of KSHV-positive PEL on the mitotic kinase, NEK2, for survival. Inhibition of NEK2 with the inhibitor, JH295, resulted in caspase 3-mediated apoptotic cell death of PEL. Furthermore, NEK2 inhibition significantly prolonged survival and reduced tumor burden in a PEL mouse model. We also demonstrate that the ABC transporter proteins, MDR1 and MRP, are most active in PEL and that inhibition of NEK2 in PEL reduced the expression and activity of these ABC transporter proteins, which are known to mediate drug resistance in cancer. Finally, we report that JH295 treatment sensitized lymphomas to other chemotherapeutic agents such as rapamycin, resulting in enhanced cancer cell death. Overall, these data offer important insight into the mechanisms underlying PEL survival and drug resistance, and suggest that NEK2 is a viable therapeutic target for PEL. SIGNIFICANCE: The mitotic kinase, NEK2, is important for the survival of KSHV-positive PEL. NEK2 inhibition resulted in PEL apoptosis and reduced tumor burden in a mouse model. NEK2 inhibition also reduced drug resistance.
Assuntos
Herpesvirus Humano 8 , Linfoma não Hodgkin , Linfoma de Efusão Primária , Masculino , Animais , Camundongos , Humanos , Feminino , Linfoma de Efusão Primária/tratamento farmacológico , Transportadores de Cassetes de Ligação de ATP , Agressão , Modelos Animais de Doenças , Quinases Relacionadas a NIMA/genéticaRESUMO
Primary effusion lymphoma (PEL) and a form of multicentric Castleman's disease (MCD) are both caused by Kaposi sarcoma herpesvirus (KSHV). There is a critical need for improved therapies for these disorders. The IL-6/JAK/STAT3 pathway plays an important role in the pathogenesis of both PEL and KSHV-MCD. We explored the potential of JAK inhibitors for use in PEL and KSHV-MCD, and found that pacritinib was superior to others in inhibiting the growth of PEL cell lines. Pacritinib induced apoptosis in PEL cells and inhibited STAT3 and NF-κB activity as evidenced by reduced amount of phosphorylated moieties. Pacritinib also inhibits FLT3, IRAK1, and ROS1; studies utilizing other inhibitors of these targets revealed that only FLT3 inhibitors exhibited similar cell growth inhibitory effects. FLT3's likely contribution to pacritinib's cell growth inhibition was further demonstrated by siRNA knockdown of FLT3. RNA sequencing and RT-PCR showed that many key host genes including cyclins and IL-6 were downregulated by pacritinib, while KSHV genes were variably altered. Finally, pacritinib suppressed KSHV viral IL-6-induced human IL-6 and IL-10 production in peripheral blood mononuclear cells, which may model an important step in KSHV-MCD pathogenesis. These results suggest that pacritinib warrants testing for the treatment of KSHV-MCD and PEL.
Assuntos
Hidrocarbonetos Aromáticos com Pontes , Hiperplasia do Linfonodo Gigante , Herpesvirus Humano 8 , Linfoma de Efusão Primária , Pirimidinas , Humanos , Interleucina-6/metabolismo , Linfoma de Efusão Primária/metabolismo , Citocinas/metabolismo , Leucócitos Mononucleares/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Virais/genética , Herpesvirus Humano 8/genética , Proliferação de CélulasRESUMO
Primary effusion lymphoma and its tissue-based subtype extracavitary/solid variant was first described in human immunodeficiency virus (HIV)-seropositive patients. We report the case of a 50-year-old HIV-seronegative male patient who presented with icterus and cholestasis. Computed tomography revealed a 80 × 56 mm abdominal mass. Fine-needle aspiration biopsy was performed from the celiac lymph nodes and pancreatic head, under endoscopic ultrasonography guidance. A duodenal endoscopic biopsy was taken from the infiltration area, and a core biopsy was performed for the portal hilar mass. All biopsies showed similar cytohistopathological features. LCA-positive lymphoid neoplasia had a plasmacytoid/anaplastic morphology and null cell phenotype. HHV-8 and Epstein-Barr virus-encoded small RNAs (EBER) were diffuse positive. The patient, who did not have an effusion, was diagnosed with an extracavitary/solid variant of primary effusion lymphoma. Virus-associated lymphoproliferative disorders should be considered in the differential diagnosis of patients without a history of immunosuppression or HIV infection.
Assuntos
Infecções por Vírus Epstein-Barr , Infecções por HIV , Linfoma de Efusão Primária , Humanos , Masculino , Pessoa de Meia-Idade , HIV , Infecções por HIV/complicações , Linfoma de Efusão Primária/diagnóstico , Linfoma de Efusão Primária/patologia , Herpesvirus Humano 4/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/patologia , BiópsiaRESUMO
Primary effusion lymphoma (PEL) is an aggressive neoplasm often diagnosed in immunosuppressed patients demonstrating peritoneal, pleural, or pericardial effusions. This high-grade lymphoma is strongly associated with human herpesvirus 8 (HHV8) infection and most of the lesions also show the presence of Epstein-Barr virus in tumor cells, which lacks CD20 expression and reveals a plasmablastic morphology and phenotype. The extracavitary or solid variant of PEL is even rarer and usually affects the lymph nodes and is currently considered a clinical manifestation of the classic PEL. In the oral cavity, extracavitary PEL is extremely rare and only a few patients have been previously reported, with no detailed clinicopathological description. The recognition of oral extracavitary PEL is even more important given the occurrence of plasmablastic lymphoma in the oral mucosa, which shares many clinical, microscopic, and phenotypic features with PEL, therefore, demanding from pathologists the search for HHV8, especially in immunosuppressed patients, and an appropriate clinical evaluation. In this report, we aim to describe a very rare extracavitary PEL affecting the palate of a 36-year-old patient and to review the literature regarding the extracavitary presentation of this aggressive lymphoma. This report demonstrates the importance of searching for HHV8 infection in oral lymphomas with plasmablastic features.
Assuntos
Infecções por Vírus Epstein-Barr , Infecções por Herpesviridae , Linfoma de Efusão Primária , Linfoma , Humanos , Adulto , Linfoma de Efusão Primária/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4 , Boca/patologiaRESUMO
OBJECTIVE: To describe cases of Kaposi's sarcoma-associated herpesvirus (KSHV)-associated multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL) in patients with HIV from a large, safety-net hospital system in Dallas, Texas, USA. METHODS: We conducted a retrospective review of patients with HIV-associated PEL and/or MCD. RESULTS: Twelve patients with PEL and 10 patients with MCD were identified. All patients were male and 17 of 20 were men who have sex with men; 66.7% of PEL patients and 50% of MCD patients had concurrent KS at the time of diagnosis; 42% of patients with PEL and 20% of patients with MCD died during the follow-up period. We noted improved survival in our cohort compared to previous studies, particularly in our PEL patients with a median survival of 11.4 months compared to 3-6-month median survival historically. Median follow-up time for MCD patients was 17.5 months. This improved survival is despite suboptimal antiretroviral therapy (ART) adherence at diagnosis, with only 50% of patients on ART at the time of MCD/PEL diagnosis. CONCLUSION: These data highlight the importance of early recognition of PEL and MCD, and the larger-scale efforts needed to better understand the pathogenetic drivers of clinical outcomes in patients affected by KSHV-related diseases.
Assuntos
Hiperplasia do Linfonodo Gigante , Infecções por HIV , Herpesvirus Humano 8 , Linfoma de Efusão Primária , Sarcoma de Kaposi , Minorias Sexuais e de Gênero , Humanos , Masculino , Feminino , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/epidemiologia , HIV , Homossexualidade Masculina , Linfoma de Efusão Primária/diagnóstico , Linfoma de Efusão Primária/epidemiologia , Linfoma de Efusão Primária/etiologia , Provedores de Redes de Segurança , Hiperplasia do Linfonodo Gigante/complicações , Hiperplasia do Linfonodo Gigante/diagnóstico , Infecções por HIV/complicaçõesRESUMO
Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus consisting of both latent and lytic life cycles. Primary effusion lymphoma (PEL) is an aggressive B-cell lineage lymphoma, dominantly latently infected by KSHV. The latent infection of KSHV is persistent and poses an obstacle to killing tumor cells. Like the "shock and kill" strategy designed to eliminate latent HIV reservoir, methods that induce viral lytic reactivation in tumor latently infected by viruses represent a unique antineoplastic strategy, as it could potentially increase the specificity of cytotoxicity in cancer. Inspired by this conception, we proposed that the induction of KSHV lytic reactivation from latency could be a potential therapeutic stratagem for KSHV-associated cancers. Oxidative stress, the clinical hallmark of PEL, is one of the most prominent inducers for KSHV reactivation. Paradoxically, we found that hydrogen peroxide (H2O2) triggers robust cytotoxic effects on KSHV-negative rather than KSHV-positive B lymphoma cells in a dose-dependent manner. Mechanistically, we identified forkhead box protein O1 (FoxO1) and FoxO3 as irrevocable antioxidant defense genes and both of them are upregulated by KSHV latent infection, which is essential for the promoted ROS scavenging in KSHV-positive B lymphoma cells. Pharmacological inhibition or functional knockdown of either FoxO1 or FoxO3 is sufficient to ablate the antioxidant ability and therefore increases the intracellular ROS level that further reverses KSHV from latency to active lytic replication in PEL cells, resulting in tremendous cell death both in vitro and in vivo. Additionally, the elevated level of ROS by inhibiting FoxO proteins further sensitizes PEL cells to ROS-induced apoptosis. Our study therefore demonstrated that the lytic reactivation of KSHV by inhibiting FoxO proteins is a promising therapeutic approach for PEL, which could be further extended to other virus-associated diseases.
Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , HIV-1 , Herpesviridae , Herpesvirus Humano 8 , Linfoma de Efusão Primária , Humanos , Antioxidantes , Peróxido de Hidrogênio , Espécies Reativas de Oxigênio , Latência ViralRESUMO
The 2022 European Association for Haematopathology/Society for Hematopathology lymphoma workshop session on cavity-based lymphomas included sixty-eight cases in seven sections. The disease entities discussed include primary effusion lymphomas (PEL), extracavitary primary effusion lymphomas and confounding entities (ECPEL), HHV8-negative B-lineage lymphomas-effusion based (EBV-negative, EBV-positive, and plasmablastic types), diffuse large B-cell lymphoma associated with chronic inflammation, fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL), breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), and other lymphomas presenting as an effusion. All entities above are discussed; however, three are delved into greater detail given the challenges with classification: ECPEL, HHV8-negative effusion-based lymphomas, and FA-DLBCL. Cases exemplifying the diagnostic difficulty in differentiating ECPEL from HHV8-positive diffuse large B-cell lymphoma and germinotropic lymphoproliferative disorder were discussed. The more recently recognized effusion-based HHV8-negative large B-cell lymphoma is explored, with several cases submitted raising the question if this subset should be carved out as a specific entity, and if so, what should be the refining diagnostic criteria. Case submissions to the FA-DLBCL section yielded one of the largest case series to date, including classic cases, cases furthering the discussion on disease sites and prognosis, as well as novel concepts to be considered in this entity. The 2022 EA4HP/SH workshop cases allowed for further confirmation of the characteristics of some of the more historically accepted cavity-based lymphomas, as well as further inquiry and debate on relatively new or evolving entities.
Assuntos
Herpesvirus Humano 8 , Linfoma Difuso de Grandes Células B , Linfoma Anaplásico de Células Grandes , Linfoma de Efusão Primária , Transtornos Linfoproliferativos , Humanos , Linfoma de Efusão Primária/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologiaRESUMO
Primary effusion lymphoma (PEL), Kaposi's sarcoma (KS), and multicentric Castleman's disease (MCD) is an uncommon group of diseases included in the same spectrum with related characteristics. The coexistence of all of them in the same individual is a rare occurrence. We present the case of a 25-year-old patient diagnosed with human immunodeficiency virus (HIV) and the development of all these related pathologies. Despite the use of intensive treatment according to the latest recommendations, the evolution was unfavorable. This case reflects the need for new therapies and research in this field.
Assuntos
Infecções por HIV , Herpesvirus Humano 8 , Linfoma de Efusão Primária , Sarcoma de Kaposi , Humanos , Adulto , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/patologia , Linfoma de Efusão Primária/complicações , Linfoma de Efusão Primária/diagnóstico , Infecções por HIV/complicaçõesRESUMO
BACKGROUND/AIM: Primary effusion lymphoma (PEL) is classified as a rare non-Hodgkin's B-cell lymphoma that is caused by Kaposi's sarcoma-associated herpesvirus (KSHV); PEL cells are latently infected with KSHV. PEL is frequently resistant to conventional chemotherapies. Therefore, the development of novel therapeutic agents is urgently required. Nigericin, a H+ and K+ ionophore, possesses unique pharmacological effects. However, the effects of nigericin on PEL cells remain unknown. MATERIALS AND METHODS: We examined the cytotoxic effects of the K+ ionophores, nigericin, nonactin, and valinomycin, on various B-lymphoma cells including PEL. We also evaluated ionophore-induced changes in signaling pathways involved in KSHV-induced oncogenesis. Moreover, the effects of nigericin on mitochondrial membrane potential and viral reactivation in PEL were analyzed. RESULTS: Although the three tested ionophores inhibited the proliferation of several B-lymphoma cell lines, nigericin inhibited the proliferation of PEL cells compared to KSHV-negative cells. In PEL cells, nigericin disrupted the mitochondrial membrane potential and caused the release of cytochrome c, which triggered caspase-9-mediated apoptosis. Nigericin also induced both an increase in phosphorylated p38 MAPK and proteasomal degradation of ß-catenin. Combination treatment of nigericin with the p38 MAPK inhibitor SB203580 potentiated the cytotoxic effects towards PEL cells, compared to either compound alone. Meanwhile, nigericin did not influence viral replication in PEL cells. CONCLUSION: Nigericin induces apoptosis in PEL cells by mitochondrial dysfunction and down-regulation of Wnt/ß-catenin signaling. Thus, nigericin is a novel drug candidate for treating PEL without the risk of de novo KSHV infection.
Assuntos
Antineoplásicos , Herpesvirus Humano 8 , Linfoma de Efusão Primária , Humanos , Linfoma de Efusão Primária/tratamento farmacológico , Linfoma de Efusão Primária/patologia , Nigericina/metabolismo , Nigericina/farmacologia , Nigericina/uso terapêutico , beta Catenina/metabolismo , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/patologia , Linhagem Celular Tumoral , Apoptose , Antineoplásicos/farmacologia , Herpesvirus Humano 8/fisiologia , Mitocôndrias , Ionóforos/metabolismo , Ionóforos/farmacologia , Ionóforos/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
A rare kind of malignant lymphoma, called primary effusion lymphoma (PEL) is associated with human herpesvirus 8 (HHV-8), and characterized by lymphomatous effusion in the bodily cavities. Although the initial clinical presentation of primary effusion lymphoma-like lymphoma (PEL-LL) is similar to that of PEL, PEL-LL is HHV-8 negative and has a favorable prognosis. A PEL-LL diagnosis was made after an 88-year-old man was admitted to our hospital with a pleural effusion. His disease regressed after effusion drainage. He demonstrated disease progression to diffuse large B-cell lymphoma after two years and ten months. Our example demonstrates that aggressive B-cell lymphoma can develop from PEL-LL.
Assuntos
Herpesvirus Humano 8 , Linfoma Difuso de Grandes Células B , Linfoma de Efusão Primária , Derrame Pleural Maligno , Masculino , Humanos , Idoso de 80 Anos ou mais , Linfoma Difuso de Grandes Células B/patologia , PrognósticoRESUMO
Adenosine-to-inosine RNA editing is a major contributor to transcriptome diversity in animals with far-reaching biological consequences. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of several human malignancies including primary effusion lymphoma (PEL). The extent of RNA editing within the KSHV transcriptome is unclear as is its contribution to the viral lifecycle. Here, we leverage a combination of biochemical and genomic approaches to determine the RNA editing landscape in host- and KSHV transcriptomes during both latent and lytic replication in PEL. Analysis of RNA editomes reveals it is dynamic, with increased editing upon reactivation and the potential to deregulate pathways critical for latency and tumorigenesis. In addition, we identify conserved RNA editing events within a viral microRNA and discover their role in miRNA biogenesis as well as viral infection. Together, these results describe the editome of PEL cells as well as a critical role for A-to-I editing in the KSHV lifecycle.
Assuntos
Herpesvirus Humano 8 , Linfoma de Efusão Primária , MicroRNAs , Sarcoma de Kaposi , Animais , Humanos , Herpesvirus Humano 8/metabolismo , Latência Viral/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Replicação Viral/genética , Regulação Viral da Expressão GênicaRESUMO
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi sarcoma (KS), the plasmablastic form of multicentric Castleman's disease, and primary effusion lymphoma. In sub-Saharan Africa, KS is the most common HIV-related malignancy and one of the most common childhood cancers. Immunosuppressed patients, including HIV-infected patients, are more prone to KSHV-associated disease. KSHV encodes a viral protein kinase (vPK) that is expressed from ORF36. KSHV vPK contributes to the optimal production of infectious viral progeny and upregulation of protein synthesis. To elucidate the interactions of vPK with cellular proteins in KSHV-infected cells, we used a bottom-up proteomics approach and identified host protein ubiquitin-specific peptidase 9X-linked (USP9X) as a potential interactor of vPK. Subsequently, we validated this interaction using a co-immunoprecipitation assay. We report that both the ubiquitin-like and the catalytic domains of USP9X are important for association with vPK. To uncover the biological relevance of the USP9X/vPK interaction, we investigated whether the knockdown of USP9X would modulate viral reactivation. Our data suggest that depletion of USP9X inhibits both viral reactivation and the production of infectious virions. Understanding how USP9X influences the reactivation of KSHV will provide insights into how cellular deubiquitinases regulate viral kinase activity and how viruses co-opt cellular deubiquitinases to propagate infection. Hence, characterizing the roles of USP9X and vPK during KSHV infection constitutes a first step toward identifying a potentially critical interaction that could be targeted by future therapeutics. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi sarcoma (KS), the plasmablastic form of multicentric Castleman's disease, and primary effusion lymphoma. In sub-Saharan Africa, KS is the most common HIV-related malignancy. KSHV encodes a viral protein kinase (vPK) that aids viral replication. To elucidate the interactions of vPK with cellular proteins in KSHV-infected cells, we used an affinity purification approach and identified host protein ubiquitin-specific peptidase 9X-linked (USP9X) as a potential interactor of vPK. Depletion of USP9X inhibits both viral reactivation and the production of infectious virions. Overall, our data suggest a proviral role for USP9X.