Novel therapeutic approaches for inhibiting CBFβ-SMMHC in inv(16) AML. (A) Small molecule and T-cell immunotherapy strategies for inhibiting CBFβ-SMMHC and their mechanisms of action. Ac, acetylation. (B) RUNX1-MYC axis in inv(16) AML cell survival. CBFβ-SMMHC tethers RUNX1, and this results in MYC activation and enhanced survival in inv(16) AML cells. Treatment of inv(16) AML cells with AI-10-49 induces an acute release of RUNX1 from CBFβ-SMMHC, increases RUNX1 occupancy at the MYC distal enhancers, replaces the SWI-SNF chromatin remodeling complex, and recruits polycomb-repressive complex 1 (PRC1), which in turn induces apoptosis by repressing MYC. E3, +1.7 Mb BRD4-mediated MYC enhancer (BDME)⁸⁰  element 3; ME1, +0.18 Mb MYC enhancer 1; ME2, +0.5 Mb MYC enhancer 2.