CRISPR/Cas9 Screens Reveal Epstein-Barr Virus-Transformed B Cell Host Dependency Factors.
Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma (BL) and immunosuppression-related lymphomas. These B cell malignancies arise by distinct transformation pathways and have divergent viral and host expression programs. To identify host dependency factors resulting from these EBV+, B cell-transformed cell states, we performed parallel genome-wide CRISPR/Cas9 loss-of-function screens in BL and lymphoblastoid ... cell lines (LCLs). These highlighted 57 BL and 87 LCL genes uniquely important for their growth and survival. LCL hits were enriched for EBV-induced genes, including viral super-enhancer targets. Our systematic approach uncovered key mechanisms by which EBV oncoproteins activate the PI3K/AKT pathway and evade tumor suppressor responses. LMP1-induced cFLIP was found to be critical for LCL defense against TNFα-mediated programmed cell death, whereas EBV-induced BATF/IRF4 were critical for BIM suppression and MYC induction in LCLs. Finally, EBV super-enhancer-targeted IRF2 protected LCLs against Blimp1-mediated tumor suppression. Our results identify viral transformation-driven synthetic lethal targets for therapeutic intervention.
Mesh Terms:
Apoptosis, Apoptosis Regulatory Proteins, B-Lymphocytes, Basic-Leucine Zipper Transcription Factors, Burkitt Lymphoma, CRISPR-Cas Systems, Cell Line, Cell Transformation, Viral, Complement Factor B, Gene Expression Regulation, Gene Knockdown Techniques, Herpesvirus 4, Human, Humans, Interferon Regulatory Factor-2, Interferon Regulatory Factors, Mutagenesis, NF-kappa B, Oncogene Proteins, Phosphatidylinositol 3-Kinases, Positive Regulatory Domain I-Binding Factor 1, Tumor Necrosis Factor-alpha
Apoptosis, Apoptosis Regulatory Proteins, B-Lymphocytes, Basic-Leucine Zipper Transcription Factors, Burkitt Lymphoma, CRISPR-Cas Systems, Cell Line, Cell Transformation, Viral, Complement Factor B, Gene Expression Regulation, Gene Knockdown Techniques, Herpesvirus 4, Human, Humans, Interferon Regulatory Factor-2, Interferon Regulatory Factors, Mutagenesis, NF-kappa B, Oncogene Proteins, Phosphatidylinositol 3-Kinases, Positive Regulatory Domain I-Binding Factor 1, Tumor Necrosis Factor-alpha
Cell Host Microbe
Date: May. 10, 2017
PubMed ID: 28494239
View in: Pubmed Google Scholar
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