Genome-wide CRISPR screens reveal synthetic lethal interaction between CREBBP and EP300 in diffuse large B-cell lymphoma
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s41419-021-03695-8.pdf
Description
Published version
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1.66 MB
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Author(s)
Nie, Man
Du, Likun
Ren, Weicheng
Joung, Julia
Ye, Xiaofei
Shi, Xi
Ciftci, Sibel
Liu, Dongbing
Wu, Kui
Zhang, Feng
Date Issued
May 2021
Journal
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Citation
Nie, Man, Du, Likun, Ren, Weicheng, Joung, Julia, Ye, Xiaofei et al. 2021. "Genome-wide CRISPR screens reveal synthetic lethal interaction between CREBBP and EP300 in diffuse large B-cell lymphoma." Cell Death & Disease, 12 (5).
Version
Final published version
Abstract
AbstractDiffuse 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.
MIT Department
McGovern Institute for Brain Research at MIT
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Massachusetts Institute of Technology. Department of Biological Engineering
Howard Hughes Medical Institute
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/s41419-021-03695-8
