Significance Genes encoding chromatin-modifying enzymes such as the histone acetyl-transferases (HATs) are often mutated in diffuse large B cell lymphoma (DLBCL), the most common lymphoma of adults. Here, we shed light on the tumor suppressive activity of HATs in human diffuse large B cell lymphoma (DLBCL) cell lines and in mice. Cell lines harboring an experimentally introduced patient mutation in the HAT CREBBP lose their MHCII expression and form tumors faster in subcutaneous and orthotopic xenograft models. Mice that lack Crebbp specifically in the germinal center B cell compartment also lose their MHCII expression in that compartment, and show hyperproliferation of germinal center B cells upon immunization, which predisposes them to MYC-driven lymphomagenesis. Our data implicate HATs as tumor suppressors in DLBCL.