(A) The paralogous MLL3 and MLL4 proteins share identical PHD, HMG, FYRN/C, and the catalytic SET domain, varying only in sequence length and the additional PHD domain in MLL3. The deubiquitinase BAP1 interacts with MLL3 through its N-terminal PHD domains (1–3) while the kinase AKT1 targets to the RXRXXS/T motif (pictured in asterisk) upstream of the MLL4 PHD4 domain. (B) BAP1 associates with the UTX-containing MLL3 complex to demethylate H3K27 tri-methylation (Me3), methylate H3K4 mono-methylation (Me1), and deubiquitinate BAP1-targeted enhancers, resulting to activated expression of tumor suppressor genes. (C) AKT1 functions downstream of the PI3K-signaling pathway to phosphorylate MLL4 and attenuate its function. Upon PI3K inhibition, both PI3K and AKT1 are inactivated while MLL4 activity is restored, resulting to activated expression of MLL4 and ER-mediated oncogenes and evasion of PI3K inhibitor treatment. Figures are created with Biorender.com.