CRISPR identifies epigenetic regulation as a key determinant of LAM-003 sensitivity. (A) Scatter plot showing enrichment of the top 20 normalized sgRNA read counts in vehicle and LAM-003–treated CRISPR pools in GeCKO sublibraries A and B. (B) Gene ontology analysis of top 20 sgRNAs. (C) Scatter plot showing enrichment of normalized sgRNA read count of KDM6A in vehicle and LAM-003–treated CRISPR pools from the combined A and B GeCKO sublibraries. Six individual sgRNAs used for targeting KDM6A are shown in red. (D) Normalized isobologram at the EC₇₅ of two FLT3-ITD–harboring cell lines treated with the EZH2 inhibitor EPZ6438 for 4 days followed by the combination of EZH2 inhibitors and LAM-003 for an additional 72 hours before viability was assayed by using CellTiter-Glo. Data points are the average of 2 independent experiments, each performed in duplicate.