Functional mapping of transcripts uniquely regulated by the azacitidine-panobinostat combination in MV4 11 cells identified p53 as an upstream regulator. Differential gene expression profiling was performed on AML cells treated with azacitidine, panobinostat or azacitidine-panobinostat combination. Reduced leukemic burden and prolonged survival was also observed in AML-193 xenografted mice treated with azacitidine-panobinostat combination. Mice treated with both drugs showed a drastic reduction in leukemic burden leading to complete remission sustained for the duration of the experimental period lasting more than 519 days. Azacitidine and panobinostat increased median survival by 26 and 6 days respectively in MV4 11 xenografted mice. Synergistic cytotoxic effect upon treatment with azacitidine and panobinostat with combination indices <1.0 was observed. We combined DNA hypomethylating agent azacitidine with histone deacetylase inhibitor panobinostat in preclinical models of childhood AML. Aberrations in epigenetic modifications contribute to leukemogenesis in childhood acute myeloid leukemia (AML).