KMT2D acetylation by CREBBP reveals a cooperative functional interaction at enhancers in normal and malignant germinal center B cells

Heterozygous inactivating mutations of the KMT2D methyltransferase and the CREBBP acetyltransferase are among the most common genetic alterations in B cell lymphoma and co-occur in 40 to 60% of follicular lymphoma (FL) and 30% of EZB/C3 diffuse large B cell lymphoma (DLBCL) cases, suggesting they may be coselected. Here, we show that combined germinal center (GC)-specific haploin-sufficiency of Crebbp and Kmt2d synergizes in vivo to promote the expansion of abnormally polarized GCs, a common preneoplastic event. These enzymes form a biochemical complex on select enhancers/superenhancers that are critical for the delivery of immune signals in the GC light zone and are only corrupted upon dual Crebbp/Kmt2d loss, both in mouse GC B cells and in human DLBCL. Moreover, CREBBP directly acetylates KMT2D in GC-derived B cells, and, consistently, its inactivation by FL/DLBCL-associated mutations abrogates its ability to catalyze KMT2D acetylation. Genetic and pharmacologic loss of CREBBP and the conse-quent decrease in KMT2D acetylation lead to reduced levels of H3K4me1, support-ing a role for this posttranslational modification in modulating KMT2D activity. Our data identify a direct biochemical and functional interaction between CREBBP and KMT2D in the GC, with implications for their role as tumor suppressors in FL/DLBCL and for the development of precision medicine approaches targeting enhancer defects induced by their combined loss.

Automated summary

Heterozygous inactivating mutations of KMT2D and CREBBP are common in B cell lymphoma, and they co-occur in a significant number of follicular lymphoma and EZB/C3 diffuse large B cell lymphoma cases. The combination of haploinsufficiency of Crebbp and Kmt2d promotes the expansion of abnormally polarized germinal centers, which is an early event in lymphoma development. These findings highlight the functional and biochemical interaction between Crebbp and Kmt2d, and its implications for the treatment of lymphomas with enhancer defects induced by their combined loss.