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PARP1 Inhibition Halts EBV+ Lymphoma Progression by Disrupting the EBNA2/MYC Axis

Giorgia Napoletani1, Samantha S Soldan1, Toshitha Kannan1

  • 1The Wistar Institute, Philadelphia, PA, 19104, USA.

Biorxiv : the Preprint Server for Biology
|July 18, 2023
PubMed

Insights

PARP1 inhibitors show potent anti-tumor effects against Epstein-Barr virus (EBV)-driven lymphomas by targeting the EBNA2/MYC pathway. This research highlights a new therapeutic strategy for EBV-associated cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Virology

Background:

  • Poly (ADP-ribose) polymerase 1 (PARP1) regulates Epstein-Barr virus (EBV) latency.
  • The therapeutic potential of PARP1 inhibitors in EBV-associated lymphomagenesis remains unexplored.

Purpose of the Study:

  • To investigate the anti-tumor effects of PARP1 inhibitors on EBV-driven lymphomas.
  • To elucidate the molecular mechanisms underlying PARP1 inhibition in EBV-driven lymphomagenesis.

Main Methods:

  • Utilized a mouse xenograft model of EBV-driven lymphoblastoid cells (LCLs).
  • Assessed the effects of the PARP1 inhibitor BMN-673 on LCLs in vivo and in vitro.
  • Analyzed transcriptional changes, oncogene expression (MYC), viral oncoprotein (EBNA2), and chromatin association of key proteins (MYC, EBNA2, p53).

Main Results:

  • PARP1 inhibition demonstrated potent anti-tumor activity against EBV-driven LCLs.
  • PARP1 inhibition led to significant transcriptional reprogramming, primarily through the downregulation of the MYC oncogene and its targets.
  • Reduced expression of viral oncoprotein EBNA2 and blocked chromatin association of MYC, EBNA2, and p53.

Conclusions:

  • PARP1 plays a critical role in EBV-driven malignant transformation.
  • The EBNA2/MYC pathway is a key target for PARP1 inhibitors in EBV-associated cancers.
  • PARP1 inhibitors represent a promising therapeutic strategy for EBNA2-driven EBV-associated malignancies.
Keywords:
BMN-673EBV-associated cancerMYCPARP1lymphoma

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