DNA-PKcs mediated transcriptional regulation of TOP2β drives chemoresistance in acute myeloid leukemia.

Anthracyclines, topoisomerase 2 enzyme poison that results in DNA damage, are the mainstay of acute myeloid leukemia (AML) treatment. However, acquired resistance to anthracyclines leads to relapse, which currently lacks effective treatment and is the cause of poor survival in AML patients. Therefore, the identification of the mechanisms underlying anthracycline resistance remains an unmet clinical need. Here, using patient-derived primary cultures and clinically relevant cellular models that recapitulate acquired anthracycline resistance in AML, we found GCN5-mediated transcriptional upregulation of DNA-PKcs in AML relapse, independent of the DNA-damage response. We demonstrated that anthracyclines failed to induce DNA damage in resistant cells owing to the loss of expression of their target enzyme-TOP2B, rendered by DNA-PKcs directly binding to its promoter upstream region as a transcription repressor. Importantly, DNA-PKcs kinase activity inhibition re-sensitized AML relapse primary cultures and cells resistant to mitoxantrone and abrogated their tumorigenic potential in a xenograft mouse model. Together, our findings identified a GCN5-DNA-PKcs-TOP2B transcriptional regulatory axis as the mechanism underlying anthracycline resistance, and demonstrated the therapeutic potential of DNA-PKcs inhibition to re-sensitize resistant AML relapse cells to anthracycline.