Genome-wide CRISPR screens reveal synthetic lethal interaction between CREBBP and EP300 in diffuse large B-cell lymphoma
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 (...
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Veröffentlicht in: | Cell death & disease 2021-04, Vol.12 (5), p.419-419, Article 419 |
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Sprache: | eng |
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Zusammenfassung: | 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
CREBBP
and
MDM2
. The dependency on
CREBBP
is associated with a balanced translocation involving
EP300
, which results in a truncated form of the protein that lacks the critical histone acetyltransferase (HAT) domain. The synthetic lethal interaction between
CREBBP
and
EP300
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
CREBBP
or
EP300
mutated cases. |
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ISSN: | 2041-4889 2041-4889 |
DOI: | 10.1038/s41419-021-03695-8 |