Follicular lymphoma (FL) and the EZB/C3 subtype of diffuse large B-cell lymphoma (DLBCL) are characterized by frequent mutations of chromatin-modifying genes, including KMT2D, CREBBP, and EZH2. Genomic analysis of serial biopsies from FL patients has allowed the reconstruction of evolutionary phylogenies and highlighted CREBBP mutations as occurring predominantly as early events in disease evolution and residing within common progenitor cells that seed relapse. Patient tumor cells with CREBBP mutations have significantly reduced MHC class II expression and perturbed T-cell responses to tumor, suggesting a role for CREBBP mutations in driving immune evasion. Knock-out and knock-down studies of Crebbp confirmed its tumor-suppressor function in animal models, but uncovered some differences compared to the phenotypes observed in association with CREBBP mutations in primary tumors. Mutations of CREBBP most often encode missense amino acid substitutions within the catalytic lysine acetyltransferase (KAT) domain rather than nonsense/frameshift variants that result in a loss of protein expression. Here I will discuss recently published and unpublished data regarding the function of CREBBP mutations in B-cell lymphoma, functional differences between classes of mutations (KAT domain missense vs. nonsense/frameshift) and between different mutational hotspots within the KAT domain. Furthermore, I will discuss how these functional insights provide a rationale for targeted therapeutic strategies in B-cell lymphoma.
Citation Format: Michael R. Green. CREBBP: Not all mutations are created equal [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA25.