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High\u2010intensity multidrug chemotherapy regimens have a limited effect on the survival of refractory or relapsed BL patients, mainly owing to the high EBV load and drug resistance. <jats:sc>l<\/jats:sc>\u2010asparaginase (\n<jats:sc>l<\/jats:sc>\u2010Asp) and etoposide (VP\u201016) play a beneficial role in EBV\u2010related lymphoproliferative diseases; however, their roles and mechanisms in BL remain unclear. In this study, we found that VP\u201016 inhibited BL cell proliferation and arrested the cell cycle at the G<jats:sub>2<\/jats:sub>\/M phase. It also induced autophagy and activated the extrinsic and intrinsic apoptotic signaling pathways in BL cells. Mechanistically, VP\u201016 inhibited c\u2010Myc expression and regulated the PI3K\/Akt\/mTOR signaling pathway. Notably, VP\u201016 also showed a specific synergistic effect with \n<jats:sc>l<\/jats:sc>\u2010Asp to induce apoptosis in EBV\u2010positive BL cells but not in EBV\u2010negative BL cells. VP\u201016 combined with \n<jats:sc>l<\/jats:sc>\u2010Asp further inhibited c\u2010Myc expression and downregulated the PI3K\/Akt\/mTOR signaling pathway. Additionally, we found that VP\u201016 inhibited the expression of latent membrane protein 1 (LMP1), and in combination with \n<jats:sc>l<\/jats:sc>\u2010Asp further decreased LMP1 expression in Raji cells. Our in vivo data also showed that the dual\u2010drug combination significantly inhibited the growth of BL tumors and prolonged the survival of mice compared to VP\u201016 alone. In conclusion, this study provides new evidence that \n<jats:sc>l<\/jats:sc>\u2010Asp may enhance the antitumor effect of VP\u201016 by inhibiting the PI3K\/Akt\/mTOR signaling pathway in EBV\u2010positive BL cells.<\/jats:p>","DOI":"10.1002\/jbt.23117","type":"journal-article","created":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T08:16:07Z","timestamp":1656317767000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>l<\/scp>\u2010Asparaginase synergizes with etoposide via the PI3K\/Akt\/mTOR pathway in Epstein\u2212Barr virus\u2010positive Burkitt lymphoma"],"prefix":"10.1002","volume":"36","author":[{"given":"Wei","family":"Sang","sequence":"first","affiliation":[{"name":"Blood Diseases Institute Xuzhou Medical University Xuzhou Jiangsu China"},{"name":"Department of Hematology The Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu China"},{"name":"Key Laboratory of Bone Marrow Stem Cell 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