Epigenetic activation of EBV BGLF4 determines antiviral-based regimen response in EBV+CNS lymphoproliferative disease - PubMed
12 hours ago
- #Epstein-Barr virus
- #CNS Lymphoma
- #Epigenetics
- Epstein-Barr virus (EBV)-associated primary central nervous system lymphoproliferative diseases (EBV+PCNSL) are aggressive with poor prognoses.
- Ganciclovir, azidothymidine, rituximab, and dexamethasone (GARD) treatment showed durable responses in PCNSL patients, linked to lytic viral protein kinases BGLF4 and BXLF1.
- RNA expression in CNSL biopsies confirmed LMP1, BXLF1, and BGLF4 but not BZLF1, indicating an incomplete lytic EBV program.
- Systemic PTLD cases showed significantly lower BXLF1 and BGLF4 expression compared to CNSL.
- BGLF4 promoter methylation was significantly lower in CNSL vs systemic PTLD (P = .0006).
- Luciferase reporter analysis identified 3 promoter activity regions in BGLF4 upstream sequence, with transcription start sites in EBV-infected cells and CNSL samples.
- CNSL-specific DNA methylation loss occurred at single CpG dinucleotides, while surrounding EBV methylation remained high.
- TET knockout and IDH1 mutant expression in a latent EBV model showed active demethylation is necessary for BGLF4 promoter activity.
- Epigenetic activation of BGLF4 in CNSL via locus-specific promoter activation may determine GARD sensitivity.