| Literature DB >> 28494239 |
Yijie Ma1, Michael J Walsh2, Katharina Bernhardt1, Camille W Ashbaugh1, Stephen J Trudeau1, Isabelle Y Ashbaugh1, Sizun Jiang2, Chang Jiang1, Bo Zhao1, David E Root3, John G Doench3, Benjamin E Gewurz4.
Abstract
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.Entities:
Keywords: CRISPR; Epstein-Barr virus; NF-kappaB; apoptosis; dependency factor; gamma-herpesvirus; interferon regulatory factor; oncoprotein; synthetic lethal; tumor virus
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Year: 2017 PMID： 28494239 PMCID： PMC8938989 DOI： 10.1016/j.chom.2017.04.005
Source DB: PubMed Journal: Cell Host Microbe ISSN： 1931-3128 Impact factor: 21.023