PML/RARα coexists within the super-enhancer regions to regulate APL-specific genes. (A) Heatmap showing abundant PML/RARα, H3K27ac, and H3K4me1 occupancy on PML/RARα binding sites, with those indicative of active enhancers highlighted. (B) PML/RARα tended to bind at enhancers with higher H3K27ac signals in APL cells, including NB4 (upper panel) and primary blasts (lower panel). Enhancers were ranked by the H3K27ac signal. Super-enhancers were defined using the ROSE methods (detailed in supplemental Methods). The bar above shows the distribution of PML/RARα binding among enhancers, in which the yellow represents the peak with PML/RARα binding and the blue for the peak without PML/RARα binding. (C) PML/RARα preferentially bound super-enhancers three- to fourfold more likely than typical enhancers in APL cells, including NB4 (upper panel) and primary blasts (lower panel). Pie plots show the percentages of PML/RARα binding within the super-enhancer regions and typical-enhancer regions. (D) SEPRTs essential for the survival of APL cells, supported by CRISPR-Cas9 screening data in NB4 cells. The left panel shows GSEA using the SEPRTs and CRISPR score. The CRISPR score was used to rank 18 661 genes in the CRISPR-Cas9 screen applied to NB4 cells. The right panel shows normalized read counts of sgRNA in NB4 cells transfected with the Cas9-CRISPR/sgRNA library before and after population doublings.