CBFB (core-binding factor subunit beta) is a transcriptional coactivator that forms a nuclear complex with RUNX proteins to regulate gene expression by RNA polymerase II 1. As an obligatory RUNT cofactor, CBFB controls T cell lineage determination and naive T cell homeostasis through interaction with lineage-determining transcription factors ThPOK and RUNX3 2. CBFB functions primarily through its association with core-binding factor complexes to activate transcription at target genes. During HIV-1 infection, CBFB is hijacked by the viral Vif protein and incorporated into cullin-5-RING E3 ubiquitin ligase complexes that catalyze ubiquitination and degradation of antiviral APOBEC3 proteins, thereby promoting viral replication 3456. This association also inhibits CBFB's transcriptional coactivator activity. CBFB alterations have significant clinical relevance in hematologic malignancies. CBFB-MYH11 translocations occur in core-binding factor acute myeloid leukemia (CBF-AML), where the fusion protein sequesters CBF-alpha in the cytoplasm and inhibits CBF-mediated transactivation, blocking hematopoietic differentiation 1. Recent proteomic analysis identified a distinct S8 subtype characterized by CBFB::MYH11 fusion 7. CBFB mutations also appear in cervical adenocarcinomas 8 and represent a potential therapeutic target for migraine 9.