RNA-seq for siPRKDC and siControl in human HL-60/MX2 mitoxantrone resistant derivative of the HL-60 cell line.

Anthracyclines, topoisomerase 2 enzyme poison that results in DNA damage, are currently used in acute myeloid leukemia (AML) treatment. Identifying the mechanisms underlying drug resistance remains an important question. Here, using a mitoxantrone-resistant cell line (HL-60/MX2), we found upregulation of DNA-PKcs, 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. However, to explore other putative dysregulated pathways and genes, we performed RNA-seq experiments on HL-60/MX2 cells after siRNA-mediated knockdown of PRKDC.