guest ::
| Home > Publications database > Epigenetic activation of EBV BGLF4 determines antiviral-based regimen response in EBV+CNS lymphoproliferative disease. |
| Home > Publications database > Epigenetic activation of EBV BGLF4 determines antiviral-based regimen response in EBV+CNS lymphoproliferative disease. |
| Journal Article | DKFZ-2026-00575 |
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
2026
Elsevier
[Amsterdam]
Abstract: Epstein-Barr virus (EBV)-associated primary central nervous system lymphoproliferative diseases (EBV+PCNSL) are aggressive conditions with poor prognoses. We previously reported durable responses in patients with PCNSL who were treated with the antivirals ganciclovir and azidothymidine, plus rituximab and dexamethasone (GARD). Responses were associated with the detection of the lytic viral protein kinases, BGLF4 and BXLF1. These antiviral activating kinases are associated with lytic EBV, however, the mechanism for expression in latently infected EBV+CNSL is unknown. Expanding on previous work, we provide long-term clinical outcome data (N = 24) and show that RNA expression analysis in CNSL tissue biopsies (n = 12) confirmed the expression of LMP1, BXLF1, and BGLF4 but not BZLF1, supporting an incomplete lytic EBV program. Control biopsies from systemic PTLD cases (N = 24) showed significantly less expression of BXLF1 and BGLF4. By quantifying DNA methylation in EBV gene promoters, we showed significantly decreased promoter methylation at BGLF4 in CNSL vs systemic PTLD cases (P = .0006). Luciferase reporter analysis of the BGLF4 upstream sequence revealed 3 regions of promoter activity, and 5' rapid amplification of complimentary DNA ends in EBV-infected cell lines and CNSL samples identified transcription start sites at these promoters. We identified CNSL-specific DNA methylation loss at single CpG dinucleotides, whereas the surrounding EBV methylation levels remained high. Lastly, TET knockout and the expression of TET1/2-suppressive mutant IDH1 in a latent HEK293 EBV model indicated that active demethylation is necessary for the activity of BGLF4 promoters. We detailed the epigenetic basis of BGLF4 expression in CNSL via locus-specific promoter activation, which may hold value for determining GARD sensitivity.
|
The record appears in these collections: |
