Dependency of DLBCL on histone acetyl transferases CREBBP and EP300

Diffuse Large B-cell Lymphoma (DLBCL) represents the most common form of B-cell non-Hodgkin Lymphoma (B-NHL), accounting for ~30% of the de-novo diagnoses and also arising as a frequent clinical evolution of Follicular Lymphoma (FL). A significant fraction of DLBCL remains incurable, underscoring the need to identify molecular mechanisms that are responsible for disease development and that can be targeted therapeutically. Work from our laboratory led to the discovery that DLBCL is frequently associated with monoallelic inactivating mutations of CREBBP and, at lower frequencies, EP300, two highly related histone and non-histone acetyltransferases (HATs). Accordingly, CREBBP has recently been shown to have a haploinsufficient tumor suppressor role during GC development. Crebbp and Ep300 mutations are mostly mutually exclusive in DLBCL, suggesting that tumor cells need either functional CREBBP or EP300 to maintain essential histone modifications. Thus, we propose that loss of EP300 in Crebbp+/- deficient cells could act in a synthetic lethal manner and this could be exploited for therapeutic targeting in these tumors.