Targeting Monoallelic CREBBP / EP300 Mutations in Germinal Center-Derived B-Cell Lymphoma with a First-in-Class Histone Acetyltransferase Activator

Inactivating, monoallelic mutations in histone acetyltransferases (HATs) CREBBP / EP300 are common in germinal center (GC) B-cell lymphomas and are implicated in derangements of the GC reaction, evasion of immune surveillance, and disease initiation. This study evaluates a first-in-class HAT activator, YF2, as a way to allosterically induce the functional HAT allele. YF2 binds to the bromo/RING domains of CREBBP/p300, increasing enzyme auto-acetylation and activation, and is selectively cytotoxic in HAT-mutated lymphoma cell lines. YF2 induces CREBBP/p300-mediated acetylation of putative targets including H3K27, p53, and BCL6. Treatment with YF2 transcriptionally activates numerous immunological pathways and increases markers of antigen presentation. Furthermore, YF2 modulates the GC reaction and increases B-cell maturation. YF2 is well tolerated in vivo and improves survival in cell line- and patient-derived xenograft lymphoma mouse models. In summary, pharmacological activation of the functional HAT allele using YF2 effectively counteracts monoallelic CREBBP / EP300 mutations in GC B-cell lymphoma.