The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry
Open accessAbstract
Childhood high-risk neuroblastomas with MYCN gene amplification are difficult to treat effectively1. 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 survival2–6, 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. This study identifies a set of critical dependency genes in MYCN-amplified neuroblastoma that make up the oncogenic transcriptional regulatory circuitry underlying cell state and tumor survival.
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Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition
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A first-generation pediatric cancer dependency map
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Metadata
- Authors
- Durbin, A. D., Zimmerman, M. W., Dharia, N. V., Abraham, B. J., Iniguez, A. B., Weichert-Leahey, N., He, S., Krill-Burger, J. M., Root, D. E., Vazquez, F., Tsherniak, A., Hahn, W. C., Golub, T. R., Young, R. A., Look, A. T., & Stegmaier, K.
- Venue
- Nature Genetics
- Published
- 2018-08-20
- Volume
- 50
- Issue
- 9
- Pages
- 1240-1246
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2886522065
- Cited by
- 283
- References
- 43
- FWCI
- 14.52
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Durbin, A. D., Zimmerman, M. W., Dharia, N. V., Abraham, B. J., Iniguez, A. B., Weichert-Leahey, N., He, S., Krill-Burger, J. M., Root, D. E., Vazquez, F., Tsherniak, A., Hahn, W. C., Golub, T. R., Young, R. A., Look, A. T., & Stegmaier, K. (2018). Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry. Nature Genetics. https://doi.org/10.1038/s41588-018-0191-z
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