Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry
Name
nihms970890.pdf
Description
Accepted version
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884.91 KB
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Adobe PDF
Checksum (MD5)
2541146679ebea82df1462e73f767ebc
Author(s)
Abraham, Brian J.
Young, Richard A.
Date Issued
August 20, 2018
Journal
Nature genetics
Publisher
Springer Science and Business Media LLC
Citation
Durbin, Adam D. et al. “Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry.” Nature genetics 50 (2018): 1240-1246 © 2018 The Author(s)
Version
Author's final manuscript
Abstract
Childhood high-risk neuroblastomas with MYCN gene amplification are difficult to treat effectively 1 . This has focused attention on tumor-specific gene dependencies that underlie tumorigenesis and thus provide valuable targets for the development of novel therapeutics. Using unbiased genome-scale CRISPR–Cas9 approaches to detect genes involved in tumor cell growth and survival 2–6 , we identified 147 candidate gene dependencies selective for MYCN-amplified neuroblastoma cell lines, compared to over 300 other human cancer cell lines. We then used genome-wide chromatin-immunoprecipitation coupled to high-throughput sequencing analysis to demonstrate that a small number of essential transcription factors—MYCN, HAND2, ISL1, PHOX2B, GATA3, and TBX2—are members of the transcriptional core regulatory circuitry (CRC) that maintains cell state in MYCN-amplified neuroblastoma. To disable the CRC, we tested a combination of BRD4 and CDK7 inhibitors, which act synergistically, in vitro and in vivo, with rapid downregulation of CRC transcription factor gene expression. This study defines a set of critical dependency genes in MYCN-amplified neuroblastoma that are essential for cell state and survival in this tumor.
Subjects
Genetics
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biology
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/s41588-018-0191-z
