Transcriptional profiling of murine germinal center (GC) B cells from GC-specific conditional Crebbp R14467H knock-in and Crebbp-knock-out mice

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 and lead to either complete protein loss or single amino acid substitutions in the acetyltransferase (KAT) domain. As a consequence, CREBBP is impaired in its ability to acetylate enhancer histones as well as non-histone proteins implicated in the germinal center (GC) reaction, the structure from which these tumors originate. However, whether truncating and missense mutations of the KAT domain are functionally equivalent remains unexplored. Using a conditional GC-specific knock-in mouse model for the highly frequent Crebbp-R1446H amino-acid change (CrebbpRH), here we show that, compared to complete Crebbp loss, missense mutants impose distinct quantitative and qualitative effects on the GC response. CrebbpRH mutation controls unique transcriptional programs leading to the pre-neoplastic expansion of GCs with abnormal architecture, increased percentage of Tfh cells, and a skewed immune response toward memory B cell differentiation. Expression of CrebbpRH, but not Crebbp loss, was by itself sufficient to initiate malignant transformation in vivo, indicating a stronger tumor-promoting activity. Our findings, together with the differential distribution of missense and truncating mutations in FL and DLBCL, have implications for the mechanisms underlying lymphomagenesis and their therapeutic targeting.