Loss of enhancer activation in CREBBP mutant lymphomas can be overcome using bispecific T-cell engagers to restore EP300 compensation

Epigenetic deregulation of cell state transitions and T-cell interactions are a hallmark of germinal center (GC)-derived B-cell lymphomas. Here we show that CREBBP and EP300 are dynamically and reciprocally loaded onto chromatin during signal-responsive cell state transitions within the GC. Lysine acetyltransferase (KAT) domain mutations of CREBBP impair CD40-responsive CREBBP chromatin loading in lymphoma cells, while inhibiting EP300 compensation, leading to enhancer inactivation. Mechanistically, the inhibition of EP300 compensation occurs via binding of limiting abundance of nuclear transcription factor by KAT mutant CREBBP. Strong CD40 signaling driven by ligand or bispecific antibody engagement of CD4 T-cells increases nuclear transcription factor abundance, allowing for EP300 compensation, and drives cell death of CREBBP mutant lymphoma cells. These observations support a model in which CREBBP KAT domain mutations have a dominant-negative effect by competing with EP300 for transcription factor, which can be overcome by saturating nuclear transcription factor abundance through enforced T-cell engagement.