Chidamide induces EBV lytic infection and acts synergistically with tenofovir eliminate EBV-positive Burkitt lymphoma .

Epstein-Barr virus (EBV) is a type of human gamma-herpesvirus, and its reactivation plays an important role in the development of EBV-driven Burkitt lymphoma (BL). Despite intensive chemotherapy, the prognosis for patients with refractory or relapsed BL remains unfavorable, and a definitive method to completely eliminate latent EBV infection is lacking. Previous studies have demonstrated that histone deacetylase (HDAC) inhibitors can induce the transition of EBV from latency to the lytic phase. The lytic activation of EBV can be inhibited by tenofovir, a potent inhibitor of DNA replication. Herein, we explored the anti-tumor effect and EBV clearance potential of a novel HDAC inhibitor called chidamide in combination with tenofovir in EBV-positive BL. In our study, chidamide demonstrated inhibitory activity against HDAC. Moreover, chidamide inhibited BL cell proliferation, arrested cell cycle progression, and induced apoptosis in BL cells primarily by regulating the MAPK pathway. Additionally, chidamide promoted the transcription of lytic genes, including BZLF1, BMRF1, and BMLF1 Compared with chidamide alone, the addition of tenofovir further induced growth arrest and apoptosis, inhibited EBV lytic genes transcription induced by chidamide alone in EBV-positive BL cells. Furthermore, our in vivo data demonstrated that the combination of chidamide and tenofovir had superior tumor-suppressive effects in a mouse model of BL cell tumors. The aforementioned findings confirm the synergistic effect of chidamide in combination with tenofovir in inducing growth inhibition and apoptosis in EBV-positive BL cells, and provided a potent and effective strategy for eliminating EBV and EBV-associated malignancies. Significance Statement High levels of EBV-DNA have consistently been associated with unfavorable progression-free survival (PFS) and overall survival (OS) for EBV-associated lymphomas. Therefore, identifying novel strategies to effectively eradicate tumor cells and eliminate the EBV virus is of utmost importance for lymphoma patients. In this study, we for the first time confirmed the synergistic efficacy of combining chidamide with tenofovir in the treatment of BL and the eradication of EBV virus.