Our current framework, in which the intrinsic variability in the functioning of the EZH2/KDM6A and MLL2/KDM5 switches might drive the dependency of specific cancer cell types (e.g., tumor-initiating/therapy-resistant cancer stem cell-like states) on certain rates of me3 editing (addition/removal) at H3K27/K4 bivalent chromatin (Fig 8) might illuminate a purely epigenetic manner to maximize the therapeutic benefits of EZH2 and KDM inhibitors for clinical management of intratumoral heterogeneity. The gene discussed is KDM6A; the disease is neoplasm.