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Nat Commun. 2018 Aug 15;9(1):3263. doi: 10.1038/s41467-018-05506-9.

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

Author information

1
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
2
Duke Cancer Institute and Center for Genomic and Computational Biology, Duke University, Durham, NC, 27708, USA.
3
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
4
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. e-gottwein@northwestern.edu.

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-κB 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.

PMID:
30111820
PMCID:
PMC6093911
DOI:
10.1038/s41467-018-05506-9
[Indexed for MEDLINE]
Free PMC Article

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