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

被引：105

作者：

Ma, Yijie ^{[1
]}

Walsh, Michael J. ^{[1
,2
]}

Bernhardt, Katharina ^{[1
]}

Ashbaugh, Camille W. ^{[1
]}

Trudeau, Stephen J. ^{[1
]}

Ashbaugh, Isabelle Y. ^{[1
]}

Jiang, Sizun ^{[1
,2
]}

Jiang, Chang ^{[1
]}

Zhao, Bo ^{[1
]}

Root, David E. ^{[3
]}

Doench, John G. ^{[3
]}

Gewurz, Benjamin E. ^{[1
,2
,3
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA

[2] Harvard Med Sch, Program Virol, Boston, MA 02115 USA

[3] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

来源：

CELL HOST & MICROBE | 2017年 / 21卷 / 05期

关键词：

NF-KAPPA-B; LATENT MEMBRANE-PROTEIN-1; ENRICHMENT ANALYSIS; SUPER-ENHANCERS; GENE-EXPRESSION; GENOME-WIDE; 3C BINDS; C-MYC; EBV; TRANSCRIPTION;

D O I：

10.1016/j.chom.2017.04.005

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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 TNF alpha-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.

引用

页码：580 / +

页数：19

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