Runt-related transcription factor 1–Core-binding factor subunit beta (RUNX1–CBFβ) protein–protein interface (RUNX1–CBFβ interface)

The Runt-related transcription factor 1–Core-binding factor subunit beta (RUNX1–CBFβ) protein–protein interface is a vital regulatory assembly required for normal hematopoiesis and the development of hematopoietic stem cells (UniProt P19022, Q13951). RUNX1 serves as the DNA-binding alpha subunit, while CBFβ acts as the non-DNA-binding beta subunit that allosterically enhances RUNX1's DNA affinity and protects it from degradation (Speck & Gilliland, Nat Rev Cancer 2002). This heterodimeric complex, known as Core Binding Factor (CBF), regulates the expression of genes essential for myeloid and lymphoid differentiation. Genetic alterations affecting this interface, such as the inv(16) translocation producing the CBFβ-SMMHC fusion protein or the t(8;21) translocation producing RUNX1-RUNX1T1, are frequent drivers of acute myeloid leukemia (AML) (PubMed: 25859045). These fusion proteins outcompete wild-type components for the interface, leading to transcriptional repression and a block in cell differentiation. Small-molecule inhibitors, such as AI-10-49, have been developed to specifically disrupt the RUNX1–CBFβ interaction, thereby displacing oncogenic fusion proteins and restoring normal transcriptional programs or inducing apoptosis in leukemic cells (Illendula et al., Science 2015). However, therapeutic application must carefully balance the inhibition of malignant cells with the potential for hematotoxicity, such as thrombocytopenia, due to the target's essential role in normal blood cell production (Cunningham et al., Cancer Cell 2012).

Other names

Core-binding factor complexRUNX1-CBFB interactionAML1-CBFB interfaceCBF complex

Inhibition of the protein-protein interaction between RUNX1 and CBFβ to disrupt the formation of the Core Binding Factor complex or to displace oncogenic fusion proteins (Science. 2015;348(6231):240-4).