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Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma.

ABSTRACT: Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus. Our understanding of PEL is poor and therefore treatment strategies are lacking. To address this need, we conducted genome-wide CRISPR/Cas9 knockout screens in eight PEL cell lines. Integration with data from unrelated cancers identifies 210 genes as PEL-specific oncogenic dependencies. Genetic requirements of PEL cell lines are largely independent of Epstein-Barr virus co-infection. Genes of the NF-?B pathway are individually non-essential. Instead, we demonstrate requirements for IRF4 and MDM2. PEL cell lines depend on cellular cyclin D2 and c-FLIP despite expression of viral homologs. Moreover, PEL cell lines are addicted to high levels of MCL1 expression, which are also evident in PEL tumors. Strong dependencies on cyclin D2 and MCL1 render PEL cell lines highly sensitive to palbociclib and S63845. In summary, this work comprehensively identifies genetic dependencies in PEL cell lines and identifies novel strategies for therapeutic intervention.

SUBMITTER: Manzano M

PROVIDER: S-EPMC6093911 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma.

Manzano Mark M Patil Ajinkya A Waldrop Alexander A Dave Sandeep S SS Behdad Amir A Gottwein Eva E

Nature communications 20180815 1

Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus. Our understanding of PEL is poor and therefore treatment strategies are lacking. To address this need, we conducted genome-wide CRISPR/Cas9 knockout screens in eight PEL cell lines. Integration with data from unrelated cancers identifies 210 genes as PEL-specific oncogenic dependencies. Genetic requirements of PEL cell lines are largely independent of Epstein-Barr virus co-infection. Genes of the NF-κB pathway ...[more]

PMID: 30111820

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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

Dataset Information

Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma.

Publications

Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma.

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