Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry

• Main Authors: Abraham, Brian J. (Author), Young, Richard A. (Author)
• Other Authors: Whitehead Institute for Biomedical Research (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor)
• Format: Article
• Language: English
• Published: Springer Science and Business Media LLC, 2020-04-29T14:41:43Z.
• Subjects: Article
• Online Access: Get fulltext

 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.