MYC Controls the Epstein-Barr Virus Lytic Switch

Mol Cell. 2020 May 21;78(4):653-669.e8. doi: 10.1016/j.molcel.2020.03.025. Epub 2020 Apr 20.


Epstein-Barr virus (EBV) is associated with multiple human malignancies. To evade immune detection, EBV switches between latent and lytic programs. How viral latency is maintained in tumors or in memory B cells, the reservoir for lifelong EBV infection, remains incompletely understood. To gain insights, we performed a human genome-wide CRISPR/Cas9 screen in Burkitt lymphoma B cells. Our analyses identified a network of host factors that repress lytic reactivation, centered on the transcription factor MYC, including cohesins, FACT, STAGA, and Mediator. Depletion of MYC or factors important for MYC expression reactivated the lytic cycle, including in Burkitt xenografts. MYC bound the EBV genome origin of lytic replication and suppressed its looping to the lytic cycle initiator BZLF1 promoter. Notably, MYC abundance decreases with plasma cell differentiation, a key lytic reactivation trigger. Our results suggest that EBV senses MYC abundance as a readout of B cell state and highlights Burkitt latency reversal therapeutic targets.

Keywords: DNA looping; MYC; herpesvirus; latency reversal; lytic reactivation; tumor virus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • B-Lymphocytes / virology
  • Burkitt Lymphoma / metabolism
  • Burkitt Lymphoma / pathology*
  • Burkitt Lymphoma / virology
  • Cell Proliferation
  • Epstein-Barr Virus Infections / genetics
  • Epstein-Barr Virus Infections / metabolism
  • Epstein-Barr Virus Infections / virology*
  • Female
  • Gene Expression Regulation, Viral
  • Herpesvirus 4, Human / physiology*
  • Host-Pathogen Interactions*
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Tumor Cells, Cultured
  • Virus Activation*
  • Virus Latency*
  • Xenograft Model Antitumor Assays


  • MYC protein, human
  • Proto-Oncogene Proteins c-myc