PHILADELPHIA — (JULY 9, 2025) — Scientists at The Wistar Institute have discovered how a key protein from the Epstein-Barr virus (EBV), EBNA-LP, fundamentally rewires the three-dimensional structure of DNA in infected B cells to promote cancer development. The research, published in Nucleic Acids Research, reveals that the viral protein unlocks restricted sections of the immune cell’s genome, enabling pathways for cancerous cell growth.
“This is the first time we’ve shown that EBNA-LP has the ability to hijack the function of the host cells, those infected by EBV, to activate regions of the genome that usually shouldn’t be activated,” said Italo Tempera, Ph.D., associate professor in the Genome Regulation and Cell Signaling Program at Wistar’s Ellen and Ronald Caplan Cancer Center and senior author of the study. “The result is that the virus reprograms B cells, making them appear younger and more plastic—critical traits for cancer adaptation.”
EBV, which infects more than 90% of the world’s population, typically causes mild or no symptoms. However, in some individuals, the virus drives serious diseases including multiple cancers and autoimmune conditions like multiple sclerosis. Tempera and his team’s findings help to explain how EBV accomplishes this transformation at the molecular level.
EBV’s EBNA-LP protein was previously believed to be a “helper” protein, without a distinct role of its own. However, Tempera and his team used a mapping technique called HiChIP (Hi-C combined with chromatin immunoprecipitation) to show that EBNA-LP has a unique function: It interacts with YY1, a protein in B cells that normally helps organize the DNA’s three-dimensional structure, and that interaction affects how the genome is folded. By changing the arrangement of the genome, the proteins enable sections of DNA to be read that would ordinarily be inaccessible.
“Think of the genome like a library with different sections,” explained Tempera. “Some books are freely accessible, while others are behind locked doors. EBNA-LP essentially cracks those doors open, making restricted genomic regions accessible when they shouldn’t be.”
This process converts mature, differentiated B cells into a more naive, stem-cell-like state. The research team found that this reprogramming increases cell plasticity, making infected cells more adaptable and responsive to signals that promote cancerous growth.
EBNA-LP joins two other viral proteins, EBNA1 and EBNA2, in affecting how B-cells’ genomes are folded. The fact that the virus has evolved multiple proteins to target the same cellular process signals that this mechanism is critical for infection success—and reveals a vulnerability that might be exploited by EBV-related cancer treatments, which are currently lacking.
“There’s a major gap in how we treat EBV-related diseases right now,” noted Tempera. “We treat the cancer symptoms or the autoimmune symptoms, but we don’t yet have a way to specifically target the virus itself. This research provides a mechanistic understanding that could lead to EBV-specific therapies.”
The results of the study also suggest that similar genome-restructuring mechanisms might occur in non-EBV cancers through genetic mutations. This creates the possibility for new, even more broadly applicable therapeutic approaches.
“Viruses don’t reinvent cellular mechanisms—they grab existing tools and use them for their own purposes. By studying how EBV manipulates these tools, we learn about fundamental processes that could be disrupted in other cancers as well,” said Tempera.
Co-authors: Davide Maestri, Lisa B. Caruso, Rachel Sklutuis, and Sarah Preston-Alp from The Wistar Institute; Jana M. Cable and Micah A. Luftig from Duke University School of Medicine; and Robert E. White from Imperial College London.
Work supported by: National Health Institutes (NIH) grants R01AI130209, R01AI182056, R01AI153508, P01 CA269043, and P30 CA010815 to I.T.; R01CA140337 to M.L and R.W; T32CA09171 to S.P.A.; and T32CA288356 to R.S., as well as Cancer Center Support Grant P30 CA010815
Publication information: EBNA Leader Protein Orchestrates Chromatin Architecture Remodeling During Epstein-Barr Virus-Induced B Cell Transformation, Nucleic Acids Research, 2025. Online publication.
s well,” said Tempera.
Co-authors: Davide Maestri, Lisa B. Caruso, Rachel Sklutuis, and Sarah Preston-Alp from The Wistar Institute; Jana M. Cable and Micah A. Luftig from Duke University School of Medicine; and Robert E. White from Imperial College London.
Work supported by: National Health Institutes (NIH) grants R01AI130209, R01AI182056, R01AI153508, P01 CA269043, and P30 CA010815 to I.T.; R01CA140337 to M.L and R.W; T32CA09171 to S.P.A.; and T32CA288356 to R.S., as well as Cancer Center Support Grant P30 CA010815
Publication information: EBNA Leader Protein Orchestrates Chromatin Architecture Remodeling During Epstein-Barr Virus-Induced B Cell Transformation, Nucleic Acids Research, 2025. Online publication.
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