Differential role of CREBBP missense and truncating mutations in germinal center development and lymphomagenesis

ABSTRACT: Truncating and missense mutations of the CREBBP gene are highly prevalent in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancies. These mutations are acquired early during tumor evolution by a common precursor cell (CPC) and lead to either complete protein loss or single amino acid substitutions in the lysine acetyltransferase (KAT) domain. As a result, CREBBP is impaired in its ability to acetylate enhancer histones and nonhistone proteins implicated in the germinal center (GC) reaction, the structure from which these tumors originate. However, whether truncating and KAT domain missense mutations are functionally equivalent in instructing the CPC remains unexplored. Using a conditional GC-specific knockin mouse model for the highly frequent CREBBP-R1446H amino acid change (CrebbpRH), we show that, compared with complete Crebbp loss, missense mutants impose distinct quantitative and qualitative effects on the GC response. CrebbpRH controls unique transcriptional programs leading to the preneoplastic expansion of GCs with abnormal architecture, increased percentage of T follicular helper cells, and a skewed immune response toward memory B-cell differentiation. The expression of CrebbpRH, but not Crebbp loss, was by itself sufficient to initiate malignant transformation, indicating a stronger tumor-promoting activity. Notably, lymphoma cells with CREBBPRH and CREBBP loss showed distinct sensitivity to CREBBP/p300 small-molecule inhibitors. Together with the differential distribution of missense and truncating mutations in FL and DLBCL, these findings have implications for the pathogenesis and therapeutic targeting of these cancers.