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

• Published in: Nature genetics Vol. 50; no. 9; pp. 1240 - 1246
• Main Authors: Durbin, Adam D., Zimmerman, Mark W., Dharia, Neekesh V., Abraham, Brian J., Iniguez, Amanda Balboni, Weichert-Leahey, Nina, He, Shuning, Krill-Burger, John M., Root, David E., Vazquez, Francisca, Tsherniak, Aviad, Hahn, William C., Golub, Todd R., Young, Richard A., Look, A. Thomas, Stegmaier, Kimberly
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2018; Nature Publishing Group
• Subjects: 13; 13/1; 13/106; 13/2; 13/31; 13/56; 13/89; 38/39; 42/41; 42/44; 45; 631/114/2163; 631/114/2785; 631/208/191; 631/67; 64/60; 692/699/67; 82/29; Acids; Agriculture; Amplification; Animal Genetics and Genomics; Animals; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer; Cancer Research; Cell Line, Tumor; Cell survival; Children; Chromatin; Circuits; CRISPR; CRISPR-Cas Systems; Dependence; Disease Models, Animal; DNA binding proteins; Down-Regulation; Drug development; Female; GATA-3 protein; Gene Amplification; Gene expression; Gene Expression Regulation, Neoplastic; Gene Function; Gene sequencing; Genes; Genetic aspects; Genomes; Genomics; High-throughput screening (Biochemical assaying); Human Genetics; Humans; Immunoprecipitation; In vivo methods and tests; Islet-1 protein; Letter; Mice; Mice, Nude; MYCN gene; N-Myc Proto-Oncogene Protein - genetics; Neuroblastoma; Neuroblastoma - genetics; Next-generation sequencing; Ontology; Phox2b protein; Proteins; Stem cells; Therapeutics; Transcription (Genetics); Transcription factors; Transcription Factors - genetics; Transcription, Genetic; Tumor cell lines; Tumorigenesis; Tumors
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-018-0191-z

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. 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.