Histone acetyltransferases in B cell development and transformation 3640

Description Gene expression is regulated by several factors including histone acetyltransferases (HATS). Two HAT family members, CREB-binding protein (CREBBP) and E1A-binding protein P300 (EP300) are required to acetylate H3K27, which plays a critical role in opening chromatin. We assessed B cell development in mice lacking either CREBBP, EP300, or both genes using flow cytometry. We observed that loss of CREBBP or EP300 results in modest alterations in B cell development. In contrast, loss of both EP300 and CREBBP resulted in a complete block in B cell development. Next, we performed scRNA-seq and scATAC Seq on B cells from WT, CREBBP-deficient, EP300-deficient, and CREBBP/EP300 DKO mice. Preliminary analysis of this dataset confirms the requirement for CREBBP or EP300 for B cell development. Interestingly, despite their putative functional redundancy, the effects of EP300 or CREBBP loss on developing B cells were quite distinct. Finally, mutations in CREBBP are commonly found in relapsed human B cell leukemia (B-ALL). To see if we could better understand this process, we crossed Stat5b-CA transgenic mice (which develop B-ALL with ∼5+/- 3% penetrance) with mice lacking one or two alleles of CREBBP. This resulted in a significant and dosed-dependent increase in the rate of leukemia onset. We are currently examining how loss of CREBBP affects different stages of B cell development and increases the penetrance and onset of B cell leukemia in our murine model.