Crebbp deletion cooperates with Bcl2 over-expression to promote B-cell lymphoma in mice

We confirmed that common CREBBP mutations in human FL result in reduced acetyltransferase activity of the protein, and modeled this loss of function by B-cell-specific deletion of one or both alleles of Crebbp in transgenic mouse models. We show that Crebbp deletion results in deficits in B-cell development, and provide the first evidence from transgenic mouse models that Crebbp inactivation can cooperate with Bcl2 over-expression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B-cells we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the regulatory regions of these genes. In contrast, B-cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions that were enriched for Myc DNA binding motifs and Myc binding. These transgenic models therefore provide important links between Crebbp inactivation and Bcl2 dependence, and a potential role for Crebbp inactivation in the induction of Myc expression. B-cells were isolated from the spleens of 3 mice per strain by magnetic bead selection and interrogated by gene expression microarray