Inactivating mutations of the CREBBP acetyltransferase are highly frequent in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most common germinal-center (GC) derived cancers. However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Here we show that CREBBP regulates enhancer/super-enhancer networks with central roles in GC/post-GC cell fate decisions, including genes involved in signal transduction by the B-cell receptor and CD40 receptor, transcriptional control of GC and plasma cell development, and antigen presentation. Consistently, Crebbp-deficient B-cells exhibit enhanced response to mitogenic stimuli and perturbed plasma cell differentiation. While GC-specific loss of Crebbp was insufficient to initiate malignant transformation, compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics of FL and DLBCL, develop clonal lymphomas recapitulating the features of the human diseases. These findings establish CREBBP as a haploinsufficient tumor suppressor gene in GC B-cells and provide insights into the mechanisms by which its loss contributes to lymphomagenesis.
- Received December 17, 2016.
- Revision received January 5, 2017.
- Accepted January 6, 2017.
- Copyright ©2017, American Association for Cancer Research.