Mus musculus Raw sequence reads. Mus musculus

Anthracyclines, topoisomerase 2 enzyme poison that results in DNA damage, are currently used inacute myeloid leukemia (AML) treatment. Identifying the mechanisms underlying drug resistanceremains an important question. Here, using a mitoxantrone-resistant cell line (HL-60/MX2), wefound upregulation of DNA-PKcs, independent of the DNA damage response. We demonstrated thatanthracyclines failed to induce DNA damage in resistant cells owing to the loss of expression of theirtarget enzyme-TOP2B, rendered by DNA-PKcs directly binding to its promoter upstream region as atranscription repressor. Importantly, DNA-PKcs kinase activity inhibition re-sensitized AML relapseprimary cultures and cells resistant to mitoxantrone and abrogated their tumorigenic potential in axenograft mouse model. However, to explore other putative dysregulated pathways and genes, weperformed RNA-seq experiments on HL-60/MX2 cells after siRNA-mediated knockdown of PRKDC.