CBFβ-SMMHC in inv(16) AML: Fusion biology, RUNX1 dysregulation, and therapeutic targeting of a leukemogenic protein-protein interaction.

Acute myeloid leukemia with inv(16) is defined by the CBFB::MYH11 fusion, which produces the chimeric protein CBFβ-SMMHC and disrupts normal core-binding factor signaling. Rather than acting through enzymatic activity, this oncoprotein promotes leukemogenesis through aberrant protein-protein interactions, most notably by binding RUNX1 with enhanced avidity through both the native CBFβ interface and fusion-specific determinants within the myosin tail. As a result, RUNX1 is functionally diverted from its normal regulatory roles, leading to widespread transcriptional and chromatin abnormalities that sustain the leukemic state. This review summarizes the structural and mechanistic basis of the CBFβ-SMMHC-RUNX1 interaction and examines how this fusion reshapes gene regulation in inv(16) AML. We discuss the development of small-molecule strategies designed to disrupt this complex, with emphasis on the fusion-selective bivalent inhibitor AI-10-49, which releases RUNX1, suppresses MYC-driven programs, and induces apoptosis in preclinical models of inv(16) leukemia. We also highlight broader RUNX/CBFβ inhibitors, alternative therapeutic vulnerabilities linked to fusion-associated cofactors and chromatin regulators, and combination approaches such as BET bromodomain inhibition that enhance antileukemic activity. Together, these findings support the CBFβ-SMMHC-RUNX1 interface as a mechanistically informative and therapeutically actionable target, and illustrate the broader potential of targeting oncogenic transcription factor complexes in core-binding factor AML.