In vivo efficacy of pharmacologic DOT1L inhibition in a rat xenograft model of DNMT3A-mutant AML. (A) H3K79me2 levels in acid-extracted histones as measured by enzyme-linked immunosorbent assay in OCI AML3 subcutaneous tumors and bone marrow from vehicle control–treated animals or animals treated with 35 or 70 mg/kg per day EPZ-5676 administered via continuous IV infusion. H3K79me2 levels were normalized to those of total histone H3 in the same sample and are plotted as a percent of the mean H3K79me2 level in tissue from the vehicle-treated group, which is set at 100%. Horizontal lines represent the mean percent H3K79me2 values for each group (N = 5 animals per cohort). (B) Relative expression of MEIS1 and HOXB3 in OCI AML3 subcutaneous tumors in vehicle control–treated mice and mice treated with 35 or 70 mg/kg per day EPZ-5676 for 21 days plotted as a percent of the mean transcript level in tumors from the vehicle-treated group, which is set at 100%. Horizontal lines represent the mean percent transcript level in each group (N = 5 animals per cohort). (C) Volume of OCI AML3 subcutaneous tumors over time in vehicle control–treated animals and animals treated with 35 or 70 mg/kg per day EPZ-5676 administered via continuous IV infusion for 21 days (N = 8 animals per cohort). Error bars represent standard deviation. CI, continuous infusion.