Agent Of Primary Effusion Lymphoma Research Articles

DExD/H Box Helicases DDX24 and DDX49 Inhibit Reactivation of Kaposi's Sarcoma Associated Herpesvirus by Interacting with Viral mRNAs.

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus that is the causative agent of primary effusion lymphoma and Kaposi’s sarcoma. In healthy carriers, KSHV remains latent, but a compromised immune system can lead to lytic viral replication that increases the probability of tumorigenesis. RIG-I-like receptors (RLRs) are members of the DExD/H box helicase family of RNA binding proteins that recognize KSHV to stimulate the immune system and prevent reactivation from latency. To determine if other DExD/H box helicases can affect KSHV lytic reactivation, we performed a knock-down screen that revealed DHX29-dependent activities appear to support viral replication but, in contrast, DDX24 and DDX49 have antiviral activity. When DDX24 or DDX49 are overexpressed in BCBL-1 cells, transcription of all lytic viral genes and genome replication were significantly reduced. RNA immunoprecipitation of tagged DDX24 and DDX49 followed by next-generation sequencing revealed that the helicases bind to mostly immediate-early and early KSHV mRNAs. Transfection of expression plasmids of candidate KSHV transcripts, identified from RNA pull-down, demonstrated that KSHV mRNAs stimulate type I interferon (alpha/beta) production and affect the expression of multiple interferon-stimulated genes. Our findings reveal that host DExD/H box helicases DDX24 and DDX49 recognize gammaherpesvirus transcripts and convey an antiviral effect in the context of lytic reactivation.

Arctigenin induces the apoptosis of primary effusion lymphoma cells under conditions of glucose deprivation.

Kaposi's sarcoma-associated herpesvirus(KSHV) is the causative agent of primary effusion lymphoma(PEL) and Kaposi's sarcoma. PEL is a type of non-Hodgkin's B-cell lymphoma, affecting immunosuppressed individuals, such as post-transplant or AIDS patients. However, since PEL is resistant to chemotherapeutic regimens, new effective treatment strategies are required. Arctigenin, a natural lignan compound found in the plant Arctium lappa, has been widely investigated as a potential anticancer agent in the clinical setting. In the present study, we examined the cytotoxic effects of arctigenin by cell viability assay and found that arctigenin markedly inhibited the proliferation of PEL cells compared with KSHV-uninfected B-lymphoma cells under conditions of glucose deprivation. Arctigenin decreased cellular ATP levels, disrupted mitochondrial membrane potential and triggered caspase-9-mediated apoptosis in the glucose-deprived PEL cells. In addition, western blot analysis using phospho-specific antibodies were used to evaluate activity changes in the signaling pathways of interest. As a result, arctigenin suppressed the activation of the extracellular signal-regulated kinase(ERK) and p38mitogen-activated protein kinase (p38MAPK) signaling pathways by inhibiting ERK and p38MAPK phosphorylation in the glucose-deprived PEL cells. We confirmed that an inhibitor of ERK (U0126) or p38MAPK (SB202190 and SB203580) suppressed the proliferation of the BC3 PEL cells compared with the KSHV-negative DG75 cells. Moreover, RT-PCR and luciferase reporter assay revealed that arctigenin and p38MAPK inhibition by SB202190 or SB203580 downregulated the transcriptional expression of unfolded protein response(UPR)‑related molecules, including GRP78 and ATF6α under conditions of glucose deprivation. Finally, we confirmed that arctigenin did not affect KSHV replication in PEL cells, suggesting that arctigenin treatment for PEL does not contribute to the risk of denovo KSHV production. These data thus indicate that arctigenin may serve as a lead compound for the development of novel and effective drugs for the treatment of PEL.

Molecular mechanisms of activating c-MET in KSHV+ primary effusion lymphoma.

The oncogenic Kaposi's sarcoma–associated herpesvirus (KSHV) is a principal causative agent of primary effusion lymphoma (PEL), which is mostly seen in immunosuppressed patients. PEL is a rapidly progressing malignancy with a median survival time of approximately 6 months even under the conventional chemotherapy. We recently report that the hepatocyte growth factor (HGF)/c-MET pathway is highly activated in PEL cells and represents a promising therapeutic target (Blood. 2015;126(26):2821-31). However, the underlying mechanisms of c-MET activation within PEL cells remain largely unknown. To solve this puzzle, here we have utilized the next generation sequencing (NGS) based bioinformatics approach to investigate the genomic landscape of the c-MET gene and we found that there's no single nucleotide variations (SNVs) occurred in the c-MET genomic regions in a cohort of PEL samples. Consistently, Sanger sequencing analysis of frequently mutated exons such as exon 10, 14 and 19 shows no mutation of these c-MET exons in PEL cell-lines, which further supports the notion that mutations are not the major mechanism responsible for c-MET activation in PEL. Further, we found that a transmembrane receptor protein, Plexin-B1, is expressed in PEL cell-lines, which is required for c-MET-mediated PEL cell survival via direct protein interaction.

Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma

AbstractKaposi sarcoma–associated herpesvirus (KSHV) is a principal causative agent of primary effusion lymphoma (PEL) with a poor prognosis in immunocompromised patients. However, it still lacks effective treatment which urgently requires the identification of novel therapeutic targets for PEL. Here, we report that the hepatocyte growth factor (HGF)/c-MET pathway is highly activated by KSHV in vitro and in vivo. The selective c-MET inhibitor, PF-2341066, can induce PEL apoptosis through cell cycle arrest and DNA damage, and suppress tumor progression in a xenograft murine model. By using microarray analysis, we identify many novel genes that are potentially controlled by HGF/c-MET within PEL cells. One of the downstream candidates, ribonucleoside-diphosphate reductase subunit M2 (RRM2), also displays the promising therapeutic value for PEL treatment. Our findings provide the framework for development of HGF/c-MET–focused therapy and implementation of clinical trials for PEL patients.

Genomic analysis of xCT-mediated regulatory network: Identification of novel targets against AIDS-associated lymphoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), a rapidly progressing malignancy mostly arising in HIV-infected patients. Even under conventional chemotherapy, PEL continues to portend nearly 100% mortality within several months, which urgently requires novel therapeutic strategies. We have previously demonstrated that targeting xCT, an amino acid transporter for cystine/glutamate exchange, induces significant PEL cell apoptosis through regulation of multiple host and viral factors. More importantly, one of xCT selective inhibitors, Sulfasalazine (SASP), effectively prevents PEL tumor progression in an immune-deficient xenograft model. In the current study, we use Illumina microarray to explore the profile of genes altered by SASP treatment within 3 KSHV(+) PEL cell-lines, and discover that many genes involved in oxidative stress/antioxidant defense system, apoptosis/anti-apoptosis/cell death, and cellular response to unfolded proteins/topologically incorrect proteins are potentially regulated by xCT. We further validate 2 downstream candidates, OSGIN1 (oxidative stress-induced growth inhibitor 1) and XRCC5 (X-ray repair cross-complementing protein 5), and evaluate their functional relationship with PEL cell survival/proliferation and chemoresistance, respectively. Together, our data indicate that targeting these novel xCT-regulated downstream genes may represent a promising new therapeutic strategy against PEL and/or other AIDS-related lymphoma.

Targeting xCT, a cystine-glutamate transporter induces apoptosis and tumor regression for KSHV/HIV-associated lymphoma

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), which represents a rapidly progressing malignancy arising in HIV-infected patients. Conventional chemotherapy for PEL treatment induces unwanted toxicity and is ineffective — PEL continues to portend nearly 100% mortality within a period of months, which requires novel therapeutic strategies. The amino acid transporter, xCT, is essential for the uptake of cystine required for intracellular glutathione (GSH) synthesis and for maintaining the intracellular redox balance. Inhibition of xCT induces growth arrest in a variety of cancer cells, although its role in virus-associated malignancies including PEL remains unclear. In the current study, we identify that xCT is expressed on the surface of patient-derived KSHV+ PEL cells, and targeting xCT induces caspase-dependent cell apoptosis. Further experiments demonstrate the underlying mechanisms including host and viral factors: reducing intracellular GSH while increasing reactive oxygen species (ROS), repressing cell-proliferation-related signaling, and inducing viral lytic genes. Using an immune-deficient xenograft model, we demonstrate that an xCT selective inhibitor, Sulfasalazine (SASP), prevents PEL tumor progression in vivo. Together, our data provide innovative and mechanistic insights into the role of xCT in PEL pathogenesis, and the framework for xCT-focused therapies for AIDS-related lymphoma in future.

Systematic Analysis of a Xenograft Mice Model for KSHV+ Primary Effusion Lymphoma (PEL)

Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), which arises preferentially in the setting of infection with human immunodeficiency virus (HIV). Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV+ PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells propagated in vivo exhibit unique biology, differing from one another or from their parental cell lines propagated through in vitro culture. Therefore, we used a KSHV+ PEL/BCBL-1 xenograft model involving non-obese diabetic/severe-combined immunodeficient (NOD/SCID) mice, and compared characteristics of effusion and solid tumors with their parent cell culture-derived counterparts. Our results indicate that although this xenograft model can be used for study of effusion and solid lymphoma observed in patients, tumor cells in vivo display unique features to those passed in vitro, including viral lytic gene expression profile, rate of solid tumor development, the host proteins and the complex of tumor microenvironment. These items should be carefully considered when the xenograft model is used for testing novel therapeutic strategies against KSHV-related lymphoma.

Targeting Sphingosine Kinase Induces Apoptosis and Regression Of Virus-Associated Lymphoma In Vivo

Background and Specific Aim Sphingosine kinase (SphK) is overexpressed by a variety of cancers, and its phosphorylation of sphingosine results in accumulation of sphingosine-1-phosphate (S1P) and activation of anti-apoptotic signal transduction. Existing data indicate a role for S1P in viral pathogenesis, but roles for SphK and S1P in virus-associated cancer progression have not been defined. The Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of primary effusion lymphoma (PEL)—a rapidly progressive tumor arising in body cavities which incurs a median survival time of around 6 months with standard therapeutic approaches. ABC294640 is an orally bioavailable small molecule inhibitor of SphK under evaluation in early-phase clinical trials, although no pre-clinical or clinical data are available for this agent for hematologic or virus-associated malignancies. Therefore, we sought to determine whether ABC294640 displays inhibitory effects for HIV/KSHV+ patient-derived PEL cells in vitro and in vivo, as well as potential mechanisms through which SphK regulates KSHV pathogenesis. Methodology Complementary in vitro assays were undertaken using RNAi and ABC294640 for targeting SphK1 and SphK2 in HIV/KSHV+ patient-derived PEL cell lines (uninfected B cell tumor lines were used as controls). qRT-PCR and immunoblots were used to quantify KSHV gene expression and signal transduction, respectively; MTT assays and flow cytometry were used to assess metabolic activity and apoptosis; and mass spectrometry was used to quantify different bioactive sphingolipid intermediates associated with SphK activity. ABC294640 was used in a murine PEL xenograft model to assess the effects of SphK inhibition on KSHV+ lymphoma progression in vivo. Results and Conclusions We find that targeting SphK induces caspase cleavage and apoptosis for KSHV+ patient-derived PEL cells in the presence or absence of co-infection with the Epstein-Barr virus (EBV), whereas uninfected B cell tumor lines are less readily affected. Validating these results, we find that systemic administration of ABC294640 induces tumor regression in the PEL xenograft model. Complimentary ex vivo and in vitro analyses revealed that ABC294640 suppresses constitutive signal transduction associated with proliferation and survival of PEL cells, and increases intracellular accumulation of pro-apoptotic sphingolipid intermediates as well as KSHV lytic genes previously associated with cancer cell death. These results justify additional studies to identify mechanisms for SphK and S1P regulation of virus-associated PEL pathogenesis. Importantly, they also justify evaluation of ABC294640 in clinical trials as a single agent, or in combination with existing approaches, for the treatment of PEL and possibly other malignancies associated with oncogenic viruses. Disclosures: No relevant conflicts of interest to declare.

Kaposi's Sarcoma-Associated Herpesvirus Kaposin B Induces Unique Monophosphorylation of STAT3 at Serine 727 and MK2-Mediated Inactivation of the STAT3 Transcriptional Repressor TRIM28

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), and the inflammation-driven neoplasm Kaposi's sarcoma (KS). A triad of processes, including abnormal proliferation of endothelial cells, aberrant angiogenesis, and chronic inflammation, characterize KS lesions. STAT3 is a key transcription factor governing these processes, and deregulation of STAT3 activity is linked to a wide range of cancers, including PEL and KS. Using primary human endothelial cells (ECs), I demonstrate that KSHV infection modulated STAT3 activation in two ways: (i) KSHV induced uncoupling of canonical tyrosine (Y) and serine (S) phosphorylation events while (ii) concomitantly inducing the phosphorylation and inactivation of TRIM28 (also known as KAP-1 or TIF-1β), a newly identified negative regulator of STAT3 activity. KSHV infection of primary ECs induced chronic STAT3 activation characterized by a shift from the canonical dual P-STAT3 Y705 S727 form to a mono P-STAT3 S727 form. Expression of the latent protein kaposin B promoted the unique phosphorylation of STAT3 at S727, in the absence of Y705, activated the host kinase mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 (MK2), and stimulated increased expression of STAT3-dependent genes, including CCL5, in ECs. TRIM28-mediated repression of STAT3 is relieved by phosphorylation of S473, and in vitro kinase assays identified TRIM28 S473 as a bona fide target of MK2. Together, these data suggest that kaposin B significantly contributes to the chronic inflammatory environment that is a hallmark of KS by unique activation of the proto-oncogene STAT3, coupled with MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28.

Kaposi sarcoma herpesvirus (KSHV)-associated lymphomas are associated with markedly elevated serum IL-10, elevated IL-6, IL-17 and circulating KSHV

Background KSHV, also called human herpesvirsus-8 (HHV8), is the etiologic agent of primary effusion lymphoma (PEL) (including extracavitary variant), and large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease (together, KSHV-associated non-Hodgkin lymphoma (KSHV-NHL). Additional KSHV-associated diseases include: Kaposi sarcoma (KS), a form of multicentric Castleman disease (KSHV-MCD), and a proposed KSHV-associated inflammatory cytokine syndrome (KICS). Like KSHV-MCD, inflammatory symptoms are common in KSHV-NHL. We compared an array of inflammatory and angiogenic cytokines, chemokines, growth factors, and select clinical laboratory values between HIV-infected patients with KSHV-NHL and other lymphomas (HIV-lymphoma).

Cisplatin Disrupts the Latency of Human Herpesvirus 8 and Induces Apoptosis in Primary Effusion Lymphoma Cells

Human herpesvirus 8 (HHV8) is the etiologic agent for primary effusion lymphoma (PEL). The aim of this study is to investigate the effects of cisplatin on the PEL cells. Cisplatin treatment induced apoptosis and inhibited the growth of PEL cells, and the effect was more profound in the HHV8-positive lymphoma cells compared with the EBV-positive lymphoma cells. Cisplatin treatment decreased the expression of HHV8 latent genes and activated p53 at serine 15 in PEL cells. Our results indicate that cisplatin can disrupt HHV8 latency and induce reactivation of p53 and highly selective treatment modality for this virally induced lymphoma.

Cooperative roles for emmprin and LYVE-1 in the regulation of chemoresistance for primary effusion lymphoma

The Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), for which cytotoxic chemotherapy represents the standard of care. The high mortality associated with PEL may be explained in part by resistance of these tumors to chemotherapy. The membrane-bound glycoprotein emmprin (CD147) enhances chemoresistance in tumors through effects on transporter expression, trafficking and interactions. Interactions between hyaluronan and hyaluronan receptors on the cell surface also facilitate emmprin-mediated chemoresistance. Whether emmprin or hyaluronan-receptor interactions regulate chemotherapeutic resistance for virus-associated malignancies is unknown. Using human PEL tumor cells, we found that PEL sensitivity to chemotherapy is directly proportional to expression of emmprin, the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and a drug transporter known as the breast cancer resistance protein/ABCG2 (BCRP), and that emmprin, LYVE-1 and BCRP interact with each other and colocalize on the PEL cell surface. In addition, we found that emmprin induces chemoresistance in PEL cells through upregulation of BCRP expression, and RNA interference targeting of emmprin, LYVE-1 or BCRP enhances PEL cell apoptosis induced by chemotherapy. Finally, disruption of hyaluronan-receptor interactions using small hyaluronan oligosaccharides reduces expression of emmprin and BCRP while sensitizing PEL cells to chemotherapy. Collectively, these data support interdependent roles for emmprin, LYVE-1 and BCRP in chemotherapeutic resistance for PEL.

Kaposi Sarcoma–Associated Herpesvirus/Human Herpesvirus 8 and Kaposi Sarcoma

Kaposi sarcoma-associated herpesvirus (KSHV) was discovered in 1994 and is now known to be a necessary but not sufficient causative agent of Kaposi sarcoma. While KSHV is likely also the causative agent of primary effusion lymphoma and multicentric Castleman's disease, its causal role has been refuted in the case of multiple myeloma, sarcoidosis, prostate cancer, and amyotrophic lateral sclerosis. The epidemiology of KSHV is both intriguing and challenging. Two epidemiologic findings are clear, but their explanation is unknown. The first is that KSHV is distributed disparately throughout the world, with the virus being common in the general population throughout Africa and the Middle East, but uncommon virtually everywhere else. The second is that even though the virus is uncommon in the general population in industrialized settings, it is disproportionately concentrated among homosexual men in these areas. KSHV has special importance to the dental profession because saliva is the body fluid that harbors it most commonly, although exactly in which ways saliva spreads the virus are not known.

Convergence of Kaposi's Sarcoma-Associated Herpesvirus Reactivation with Epstein-Barr Virus Latency and Cellular Growth Mediated by the Notch Signaling Pathway in Coinfected Cells

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL). All PEL cell lines are infected with KSHV, and 70% are coinfected with Epstein-Barr virus (EBV). KSHV reactivation from latency requires promoter-specific transactivation by the KSHV Rta protein through interactions with RBP-Jk (CSL), the cellular DNA-binding component of the Notch signal transduction pathway. EBV transformation of primary B cells requires EBV nuclear antigen 2 (EBNA-2) to interact with RBP-Jk to direct the latent viral and cellular gene expression program. Although KSHV Rta and EBV EBNA-2 both require RBP-Jk for transactivation, previous studies have suggested that RBP-Jk-dependent transactivators do not function identically. We have found that the EBV latent protein LMP-1 is expressed in less than 5% of KSHV(+)/EBV(+) PEL cells but is induced in an Rta-dependent fashion when KSHV reactivates. KSHV Rta transactivates the EBV latency promoters in an RBP-Jk-dependent fashion and forms a ternary complex with RBP-Jk on the promoters. In B cells that are conditionally transformed by EBV alone, we show that KSHV Rta complements a short-term EBNA-2 growth deficiency in an autocrine/paracrine manner. Complementation of EBNA-2 deficiency by Rta depends on RBP-Jk and LMP-1, and Rta transactivation is required for optimal growth of KSHV(+)/EBV(+) PEL lines. Our data suggest that Rta can contribute to EBV-driven cellular growth by transactivating RBP-Jk-dependent EBV latency genes. However, our data also suggest that EBNA-2 and Rta induce distinct alterations in the cellular proteomes that contribute to the growth of infected cells.

KSHV-transformed primary effusion lymphoma cells induce a VEGF-dependent angiogenesis and establish functional gap junctions with endothelial cells

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of primary effusion lymphoma (PEL) and of Kaposi's sarcoma. PEL is an aggressive proliferation of B cells with poor prognosis. We evaluated both in vitro and in vivo the potential role of angiogenic factors secreted by PEL cells, that is, their interaction with endothelial cells and their implication in the invasive behavior of tumoral cells. In vitro, PEL-induced angiogenesis is dependent on vascular endothelial growth factor (VEGF) and VEGF receptors. However, although PEL cells produce VEGF and basic fibroblast growth factor (b-FGF) transcripts, they only secrete VEGF in vitro. In vivo, very high levels of both VEGF and b-FGF were found in the ascitic fluid of NOD/SCID mice injected with PEL cells. We then show evidence of cell adhesion and gap junction-mediated heterocellular communication between PEL cells and endothelial cells. Finally, we show that PEL cells extravasate through the endothelial barrier and that the specific tyrosine kinase inhibitor of VEGF receptors, PTK-787/ZK-222584, the anti-VEGF antibody, bevacizumab or the gap junction inhibitor 18-alpha-glycyrrhetinic acid, partially attenuate PEL cell extravasation. Angiogenesis, cell adhesion and communication likely contribute to the development of PEL and represent potential therapeutic targets.

PS-341 or a combination of arsenic trioxide and interferon-α inhibit growth and induce caspase-dependent apoptosis in KSHV/HHV-8-infected primary effusion lymphoma cells

Kaposi's sarcoma (KS)-associated herpes virus (KSHV) is the causative agent of primary effusion lymphoma and of KS. Primary effusion lymphoma (PEL) is an aggressive proliferation of B cells. Conventional chemotherapy has limited benefits in PEL patients, and the prognosis is very poor. We previously reported that treatment of human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma cells either with arsenic trioxide (As) combined to interferon-alpha (IFN-alpha) or with the bortezomib (PS-341) proteasome inhibitor induces cell cycle arrest and apoptosis, partly due to the reversal of the constitutive nuclear factor-kappaB (NF-kappaB) activation. PEL cells also display an activated NF-kappaB pathway that is necessary for their survival. This prompted us to investigate the effects of PS-341, or of the As/IFN-alpha combination on PEL cells. A dramatic inhibition of cell proliferation and induction of apoptosis was observed in PS-341 and in As/IFN-alpha treated cells. This was associated with the dissipation of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and was reversed by the z-VAD caspase inhibitor. PS-341 and As/IFN-alpha treatment abrogated NF-kappaB translocation to the nucleus and decreased the levels of the anti-apoptotic protein Bcl-X(L). Altogether, these results provide a rational basis for a future therapeutic use of PS-341 or combined As and IFN-alpha in PEL patients.

Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas

Kaposi's sarcoma herpesvirus (KSHV) is the etiologic agent for primary effusion lymphoma (PEL), a non-Hodgkin type lymphoma manifesting as an effusion malignancy in the affected individual. Although KSHV has been recognized as a tumor virus for over a decade, the pathways for its tumorigenic conversion are incompletely understood, which has greatly hampered the development of efficient therapies for KSHV-induced malignancies like PEL and Kaposi's sarcoma. There are no current therapies effective against the aggressive, KSHV-induced PEL. Here we demonstrate that activation of the p53 pathway using murine double minute 2 (MDM2) inhibitor Nutlin-3a conveyed specific and highly potent activation of PEL cell killing. Our results demonstrated that the KSHV latency-associated nuclear antigen (LANA) bound to both p53 and MDM2 and that the MDM2 inhibitor Nutlin-3a disrupted the p53-MDM2-LANA complex and selectively induced massive apoptosis in PEL cells. Together with our results indicating that KSHV-infection activated DNA damage signaling, these findings contribute to the specificity of the cytotoxic effects of Nutlin-3a in KSHV-infected cells. Moreover, we showed that Nutlin-3a had striking antitumor activity in vivo in a mouse xenograft model. Our results therefore present new options for exploiting reactivation of p53 as what we believe to be a novel and highly selective treatment modality for this virally induced lymphoma.

Human Herpesvirus 8 (HHV-8) in the Pathogenesis of Kaposi's Sarcoma and Other Diseases

The discovery of Kaposi's Sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/HHV-8) and subsequent studies of this virus have provided a body of evidence that support the concept that this is an etiologic agent for Kaposi's sarcoma (KS). Several studies have indicated that this virus may also be a causal agent for primary effusion lymphoma (PEL) and Castleman's disease as well. First generation serologic assays for HHV-8 have now been developed. The preponderance of data suggest that the incidence of HHV-8 infection is highest in populations at risk for KS: male homosexuals, immunosuppressed patients, and those who live in endemic regions. HHV-8 encodes for functional homologs of human proteins that may play a role in the development of disease. As we learn more about the steps by which this virus can lead to KS and/or other diseases, rational therapies and preventative strategies may be possible.