Targeting ribonucleotide reductase by 3-AP in primary effusion lymphoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE91389 | GEO | 2018/01/01
SECONDARY ACCESSION(S): PRJNA357028
REPOSITORIES: GEO
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Project description:KSHV is a principal causative agent of primary effusion lymphoma (PEL). Despite this knowledge about the close relationship between HGF/c-MET network and solid tumors development, the role of HGF/c-MET in KSHV-related malignancies remains mostly unclear. We report that HGF/c-MET pathway is highly active within KSHV+ PEL cells and plays important role in tumor cell survival/growth. Targeting HGF/c-MET by a selective inhibitor, PF-2341066, significantly induces PEL apoptosis through a complex of underlying mechanisms, including cell-cycle arrest and DNA damage. By using microarray analysis, we have identified the global gene profile controlled by HGF/c-MET pathway within KSHV+ PEL cell-lines and several novel âdruggableâ candidates closely related to cancer cell survival/growth. Finally, we found that targeting HGF/c-MET pathway by PF-2341066 effectively prevents PEL tumor expansion and/or reduce established lymphoma progression in vivo. PEL cells were treated with vehicle control or c-MET inhibitor PF-2341066 (0.8 µM) for 24 h, and the gene expression signature was compared to respective vehicle controls
2016-01-05 | E-GEOD-70594 | biostudies-arrayexpress
Project description:KSHV is a principal causative agent of primary effusion lymphoma (PEL). Despite this knowledge about the close relationship between HGF/c-MET network and solid tumors development, the role of HGF/c-MET in KSHV-related malignancies remains mostly unclear. We report that HGF/c-MET pathway is highly active within KSHV+ PEL cells and plays important role in tumor cell survival/growth. Targeting HGF/c-MET by a selective inhibitor, PF-2341066, significantly induces PEL apoptosis through a complex of underlying mechanisms, including cell-cycle arrest and DNA damage. By using microarray analysis, we have identified the global gene profile controlled by HGF/c-MET pathway within KSHV+ PEL cell-lines and several novel “druggable” candidates closely related to cancer cell survival/growth. Finally, we found that targeting HGF/c-MET pathway by PF-2341066 effectively prevents PEL tumor expansion and/or reduce established lymphoma progression in vivo.
2016-01-05 | GSE70594 | GEO
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:RNA editing is a major contributor to transcriptome diversity with far reaching biological consequences. Adenosine to Inosine (A-to-I) RNA editing is the most common type of RNA editing in animals and is carried out by a family of proteins called adenosine deaminases acting on RNAs (ADARs). 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 in PEL is unclear as is its contribution to regulating the KSHV lifecycle. Herein, we leverage a combination of biochemical and genomic approaches to determine the RNA editing landscape in host- and KSHV transcriptomes during reactivation in PEL. Analysis of host editomes indicates the editing efficiency is increased in reactivation and by analyzing BCBL1 and BC-3 editomes, we discover conserved as well as cell type specific editing events. In addition, we de novo predict and validate viral editing sites within KSHV pre-miR-K12-4. Editing at the stem region regulates miRNA biogenesis while editing within the seed region of mature miR-K12-3p regulates miRNA target specificity and viral transmission. Together, these results expand the transcriptome of PEL cells and describe a role for A-to-I editing KSHV miRNA biogenesis and target specificity.
2023-02-24 | GSE212350 | GEO
Project description: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.
2020-10-13 | GSE154900 | GEO
Project description:Primari effusion lymphoma are (PEL) patient-derived transformed B-cells harboring latent Kaposi's sarcoma-associated herpesvirus (KSHV). The treatment of PEL cells with valproic acid (VA) leads to reactivation of KSHV and viral lytic replication. The aim of this project is to evaluate the effect of KSHV lytic infection on expression of the host transcriptome.
2021-11-08 | GSE179727 | GEO
Project description:Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and frequently also harbors Epstein-Barr virus (EBV). The expression of KSHV- and, often, EBV-encoded microRNAs (miRNAs) in PELs suggests a role for these miRNAs in viral latency and lymphomagenesis. Here we report the direct and transcriptome-wide identification of miRNA target sites for all miRNAs expressed in PEL cell lines. The resulting dataset revealed that KSHV miRNAs directly target more than 2000 cellular mRNAs encoding proteins that function in pathways with relevance to KSHV pathogenesis. Moreover, ~50% of these mRNAs are also targeted by EBV miRNAs, via distinct binding sites. In addition to a known viral analog of miR-155, we show that KSHV encodes a viral miRNA that mimics cellular miR-142-3p function. In summary, these experiments identify an extensive list of mRNAs targeted by KSHV miRNAs and indicate that these are likely to strongly influence viral replication and pathogenesis. small RNA sequencing, 3 samples Ago2 (EIF2C2) PAR-CLIP, 2 samples
2011-11-16 | E-GEOD-32109 | biostudies-arrayexpress
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:Primary Effusion Lymphoma (PEL) is a Diffuse-Large B-cell Lymphoma (DLBCL) with poor prognosis. 100% of PEL carry the genome of Kaposi's Sarcoma-associated herpesvirus (KSHV) and approximately half are co-infected with Epstein-Barr virus (EBV). We profiled genomic aberrations in PEL using the Affymetrix 6.0 SNP array. This identified for the first time individual genes that are altered in PEL. 10/13 (76%) samples were deleted for both the fragile site tumor suppressors WWOX and FHIT. Alterations were also observed in: DERL1, ETV1, RASA4, TPK1, TRIM56 and VPS41 genes, which are yet to be characterized for their roles in cancer. Co-infection with EBV was associated with significantly fewer gross genomic aberrations. PEL could be segregated into EBV positive and EBV negative clusters on the basis of host chromosome alterations. The genomic signature of PEL cells in culture was analogous to those explanted from xenograft tumors. This suggests a model in which both host and virus contribute to the PEL phenotype. 17 samples (no replicates) were analyzed using Partek Genomic Suite software
2011-06-23 | E-GEOD-25839 | biostudies-arrayexpress