Efficacy of bortezomib in a direct xenograft model of primary effusion lymphoma
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE22594 | GEO | 2010/07/20
SECONDARY ACCESSION(S): PRJNA128369
REPOSITORIES: GEO
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Project description:Primary effusion lymphoma is an aggressive B-cell lymphoma most commonly diagnosed in HIV-positive patients and universally associated with Kaposi’s sarcoma-associated herpesvirus (KSHV). Chemotherapy treatment of PEL yields only short-term remissions in the vast majority of patients yet efforts to develop superior therapeutic approaches have been impeded by lack of animal models that more accurately mimic human disease. To address this issue we developed a direct xenograft model, UM-PEL-1, by transferring freshly-isolated human PEL cells into the peritoneal cavities of NOD/SCID mice without in vitro cell growth. We utilized this model to show that bortezomib induces PEL remission and extends overall survival of mice bearing lymphomatous effusions. Transcriptome analysis by genomic arrays revealed that bortezomib downregulated cell cycle progression, DNA replication, and Myc-target genes. The microarray analysis was conducted on mice bearing UM-PEL-1 xenografts after treatment for 24 hours with PBS or bortezomib. Both arms of the experiment had three mice and the RNA was pooled from the three treated mice for gene expression analysis.
2010-07-20 | E-GEOD-22594 | biostudies-arrayexpress
Project description:Primary effusion lymphomas (PELs) are specifically associated with KSHV/HHV-8 infection, and most frequently occur in HIV-positive individuals as lymphomatous effusions in the serous cavities without a detectable solid tumor mass. Most PELs have concomitant EBV infection, suggesting that EBV is an important pathogenetic co-factor, although other as yet unidentified cofactors, such as cellular genetic alterations, are also likely to play a role. Lymphomatous effusions that lack KSHV also occur; these are frequently EBV-associated in the setting of HIV infection. Here we used gene expression profile analysis to determine the viral impact on cellular gene expression and the pathogenesis of these lymphomatous effusions. We used the Affymetrix HG-U133A microarray to analyze the gene expression profile of these effusion lymphomas (three virologic groups: KSHV-positive EBV-positive PELs, KSHV-positive EBV-negative PELs and KSHV-negative EBV-positive lymphomatous effusions). Nine cell lines derived from patients with lymphomatous effusions (three from each virologic group and each cell line was done in duplicates.) and three PEL patient samples were used in the study. Our results suggest that KSHV-positive PELs are very different from KSHV-negative lymphomatous effusions, and the genes that are differentially expressed include apoptosis regulators, cell cycle regulators, transcriptional factors and signal transduction regulators. KSHV clearly plays a dominant role in the phenotype of PEL. Within the KSHV-positive PELs, two subgroups can be identified, which were correlated with their EBV viral status. Among these genes (45 gene probes), four were regulators of the MAP kinase pathway that were up-regulated in the KSHV-positive, EBV-negative PELs, suggesting that in the absence of EBV, events that lead to the activation of the MAP kinase pathway may act as a cofactor for the development of PEL. Next we determined whether we could predict the viral status of the three primary patient cases of PEL based on the 45 gene probes that were differentially expressed in KSHV-positive cell lines according to EBV status (pt. 1: KSHV-positive, EBV-positive; Pt. 2: KSHV-positive, low proportion of EBV-positive; pt. 3: KSHV-positive EBV-negative), and we could.<br><br>Samples:<br>KSHV-positive EBV-positive cell lines: BC-1, BC-2, BC-5 <br>KSHV-positive EBV-negative cell lines: BC-3, BCBL-1, PEL-5 <br>KSHV-negative EBV-positive cell lines: IBL4, SM1, BCKN-1 <br>Patient 1: KSHV-positive, EBV-positive <br>Patient 2: KSHV-positive, EBV-positive (low number of positive cells) <br>Patient 3: KSHV-positive, EBV-negative.
2007-08-25 | E-GEOD-2149 | biostudies-arrayexpress
Project description:Primary effusion lymphomas (PELs) are specifically associated with KSHV/HHV-8 infection, and most frequently occur in HIV-positive individuals as lymphomatous effusions in the serous cavities without a detectable solid tumor mass. Most PELs have concomitant EBV infection, suggesting that EBV is an important pathogenetic co-factor, although other as yet unidentified cofactors, such as cellular genetic alterations, are also likely to play a role. Lymphomatous effusions that lack KSHV also occur; these are frequently EBV-associated in the setting of HIV infection. Here we used gene expression profile analysis to determine the viral impact on cellular gene expression and the pathogenesis of these lymphomatous effusions. We used the Affymetrix HG-U133A microarray to analyze the gene expression profile of these effusion lymphomas (three virologic groups: KSHV-positive EBV-positive PELs, KSHV-positive EBV-negative PELs and KSHV-negative EBV-positive lymphomatous effusions). Nine cell lines derived from patients with lymphomatous effusions (three from each virologic group and each cell line was done in duplicates.) and three PEL patient samples were used in the study. Our results suggest that KSHV-positive PELs are very different from KSHV-negative lymphomatous effusions, and the genes that are differentially expressed include apoptosis regulators, cell cycle regulators, transcriptional factors and signal transduction regulators. KSHV clearly plays a dominant role in the phenotype of PEL. Within the KSHV-positive PELs, two subgroups can be identified, which were correlated with their EBV viral status. Among these genes (45 gene probes), four were regulators of the MAP kinase pathway that were up-regulated in the KSHV-positive, EBV-negative PELs, suggesting that in the absence of EBV, events that lead to the activation of the MAP kinase pathway may act as a cofactor for the development of PEL. Next we determined whether we could predict the viral status of the three primary patient cases of PEL based on the 45 gene probes that were differentially expressed in KSHV-positive cell lines according to EBV status (pt. 1: KSHV-positive, EBV-positive; Pt. 2: KSHV-positive, low proportion of EBV-positive; pt. 3: KSHV-positive EBV-negative), and we could. Samples: KSHV-positive EBV-positive cell lines: BC-1, BC-2, BC-5 KSHV-positive EBV-negative cell lines: BC-3, BCBL-1, PEL-5 KSHV-negative EBV-positive cell lines: IBL4, SM1, BCKN-1 pt. 1: KSHV-positive, EBV-positive pt. 2: KSHV-positive, EBV-positive (low number of positive cells) pt. 3: KSHV-positive, EBV-negative Keywords: other
2005-01-16 | GSE2149 | GEO
Project description:Infection of Kaposi's sarcoma associated herpes virus (KSHV) has been linked to the development of primary effusion lymphoma (PEL), which is characterized by the loss of expression of B cell markers and effusions in the body cavities. This unique clinical feature of PEL has been attributed to their distinctive gene expression profile which shows overexpression of genes in various signaling pathways. KSHV-encoded latent protein vFLIP K13 has been shown to promote the survival and proliferation of PEL cells. In this study, we have employed gene array analysis followed by bioinformatics analysis of coordinated transcriptional factors network as well as biological pathways to characterize the effect of K13 on PEL-derived BCBL1 cells. We observed that genes associated with Cytokine signaling, Cell death, NF-kappaB and Cell adhesion pathways were differentially regulated by K13. We used computational approach complemented with microarrays to detail the global gene expression and identified distinct classes of differentially regulated genes in various cellular processes. We employed gene array analysis followed by bioinformatics analyses of coordinated transcriptional factors network as well as biological pathways to characterize the effect of K13 on in PEL-derived BCBL1 cells.
2012-05-20 | E-GEOD-37355 | biostudies-arrayexpress
Project description:Infection of Kaposi's sarcoma associated herpes virus (KSHV) has been linked to the development of primary effusion lymphoma (PEL), which is characterized by the loss of expression of B cell markers and effusions in the body cavities. This unique clinical feature of PEL has been attributed to their distinctive gene expression profile which shows overexpression of genes in various signaling pathways. KSHV-encoded latent protein vFLIP K13 has been shown to promote the survival and proliferation of PEL cells. In this study, we have employed gene array analysis followed by bioinformatics analysis of coordinated transcriptional factors network as well as biological pathways to characterize the effect of K13 on PEL-derived BCBL1 cells. We observed that genes associated with Cytokine signaling, Cell death, NF-kappaB and Cell adhesion pathways were differentially regulated by K13. We used computational approach complemented with microarrays to detail the global gene expression and identified distinct classes of differentially regulated genes in various cellular processes.
2012-05-21 | GSE37355 | GEO
Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) causes the B cell malignancy primary effusion lymphoma (PEL). We have previously shown that cultured PEL cell lines require expression of the cellular FLICE inhibitory protein (cFLIP) for survival (Manzano et al., Nat Comm 2018), although KSHV encodes a viral homolog of this protein (vFLIP). Here we employed genome-wide CRISPR/Cas9 synthetic rescue screens to identify loss of function perturbations that can compensate for cFLIP knockout/knockdown.
2022-08-10 | GSE210445 | GEO
Project description:To identify differentially expressed human and viral miRNAs across a panel of B-cell lines, including several primary effusion lymphomas (PEL). Gammaherpesvirus and host cell microRNAs (miRNAs) together modulate gene expression in normal and malignant cells. Using microRNA microarrays, we determined the expression of mature viral and host cellular miRNAs in a series of B cell tumours that include Kaposi’s Sarcoma-associated herpesvirus (KSHV) infected Primary Effusion Lymphoma (PEL) and Epstein-Barr virus (EBV) infected Burkitt’s lymphoma (BL) cell lines. We show that 35 host miRNAs were constitutively expressed in all the B cell lymphomas and differences in viral miRNA expression were evident between herpesvirus positive tumour types. Furthermore, we show that in PEL, miR-221 and miR-222 expression is defective due to a lack of transcript expression rather than mutation in the miRNA encoding loci. Absence of miR-221 and miR-222 resulted in the enhanced expression of the known target gene p27 (CDKN1B) and reintroduction of miR221 in PEL reduces p27 protein expression.
2015-12-05 | GSE18437 | GEO
Project description:Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma arising from Kaposi sarcoma-associated herpesvirus (KSHV)/human herpesvirus-8 (HHV-8) infection. PEL shows invasive behavior, causing body cavity effusions without apparent solid tumors. The typical prognosis and clinical course of patients with PEL are poor and potentially lethal. Clarification of the pathogenic mechanisms of PEL is urgently needed in order to develop novel therapies. PEL cells generally lack B-cell surface markers such as CD19, and we therefore hypothesized that the B-cell transcription factor, PAX5, would be down-regulated in PEL. PAX5 is expressed 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 methylation of the PAX5 promoter region. 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 clarify the in vivo function of PAX5, we analyzed the restoration of PAX5 in a PEL xenograft model using severely immunodeficient, NOD/SCID/Jak3-deficient (NOJ) mice. The ascites volume and organ invasions were significantly suppressed by PAX5 restoration. Reduction of PAX5 has a critical role in the oncogenesis of PEL, and PAX5 is a tumor suppressor in PEL. Targeting PAX5 could represent a novel therapeutic approach for patients with PEL.
2024-08-02 | GSE160276 | GEO
Project description:Non-Hodgkin lymphomas (NHL) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely upregulated in different NHL subtypes. Using Multiplexed Inhibitor Bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely upregulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi’s sarcoma-associated herpesvirus (KSHV).
2019-07-11 | PXD012087 | Pride
Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) causes the B cell malignancy primary effusion lymphoma (PEL). Here we performed mRNA sequencing to characterize the mRNA expression profile of the primary effusion lymhoma (PEL) cell line BC-1.
2022-08-10 | GSE210446 | GEO