MLLârearranged acute lymphoblastic leukemia (ALL) represents a highly aggressive ALL subtype, characterized by aberrant DNA methylation patterns. DNA methyltransferase inhibitors, such as decitabine have previously been demonstrated to be effective in eradicating MLLârearranged ALL cells in vitro.
Here, we assessed the in vivo antiâleukemic potential of lowâdose DNA methyltransferase inhibitor decitabine using a xenograft mouse model of human MLLârearranged ALL. Furthermore, we explored whether prolonged exposure to lowâdose decitabine could chemoâsensitize MLLârearranged ALL cells toward conventional chemotherapy as well as other known epigeneticâbased and antiâneoplastic compounds.
Our data reveal that decitabine prolonged survival in xenograft mice of MLLârearranged ALL by 8.5 days (PÂ =Â .0181), but eventually was insufficient to prevent leukemia outâgrowth, based on the examination of the MLLAF4 cell line SEM. Furthermore, we observe that prolonged pretreatment of lowâdose decitabine mildly sensitized toward the conventional drugs prednisolone, vincristine, daunorubicin, asparaginase, and cytarabine in a panel of MLLârearranged cell lines. Additionally, we assessed synergistic effects of decitabine with other epigeneticâbased or anticancer drugs using highâthroughput drug library screens. Validation of the top hits, including histone deacetylase inhibitor panobinostat, BCL2 inhibitor Venetoclax, MEK inhibitor pimasertib, and receptor tyrosine kinase foretinib, revealed additive and moderate synergistic effects for the combination of each drug together with decitabine in a cell lineâdependent manner.