Genome-wide CRISPR screens reveal synthetic lethal interaction between CREBBP and EP300 in diffuse large B-cell lymphoma

<jats:title>Abstract</jats:title><jats:p>Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoid malignancy and a highly heterogeneous disease. In this study, we performed whole-genome and transcriptome sequencing, and a genome-wide CRISPR-Cas9-knockout screen to study an activated B-cell-like DLBCL cell line (RC-K8). We identified a distinct pattern of genetic essentialities in RC-K8, including a dependency on <jats:italic>CREBBP</jats:italic> and <jats:italic>MDM2</jats:italic>. The dependency on <jats:italic>CREBBP</jats:italic> is associated with a balanced translocation involving <jats:italic>EP300</jats:italic>, which results in a truncated form of the protein that lacks the critical histone acetyltransferase (HAT) domain. The synthetic lethal interaction between <jats:italic>CREBBP</jats:italic> and <jats:italic>EP300</jats:italic> genes, two frequently mutated epigenetic modulators in B-cell lymphoma, was further validated in the previously published CRISPR-Cas9 screens and inhibitor assays. Our study suggests that integration of the unbiased functional screen results with genomic and transcriptomic data can identify both common and unique druggable vulnerabilities in DLBCL and histone acetyltransferases inhibition could be a therapeutic option for <jats:italic>CREBBP</jats:italic> or <jats:italic>EP300</jats:italic> mutated cases.</jats:p>