CRISPR/Cas9 Screens Reveal Epstein-Barr Virus-Transformed B Cell Host Dependency Factors

Publication date: 10 May 2017
Source:Cell Host & Microbe, Volume 21, Issue 5
Author(s): Yijie Ma, Michael J. Walsh, Katharina Bernhardt, Camille W. Ashbaugh, Stephen J. Trudeau, Isabelle Y. Ashbaugh, Sizun Jiang, Chang Jiang, Bo Zhao, David E. Root, John G. Doench, Benjamin E. Gewurz
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.

Graphical abstract

Teaser

Ma et al. perform CRISPR loss-of-function screens to systematically identify host dependency factors critical for Epstein-Barr virus (EBV)-infected lymphoblastoid and Burkitt lymphoma B cell growth and survival. They identify multiple non-redundant mechanisms by which EBV prevents apoptotic responses to oncogene stress in transformed B cells, and identify key EBV-induced synthetic lethal targets.


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