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

Abstract

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.

• Authors: Adam D Durbin, Mark W Zimmerman, Neekesh V Dharia, Brian J Abraham, Amanda Balboni Iniguez, Nina Weichert-Leahey, Shuning He, John M Krill-Burger, David E Root, Francisca Vazquez, Aviad Tsherniak, William C Hahn, Todd R Golub, Richard A Young, A Thomas Look, Kimberly Stegmaier
• Journal: Nature genetics (Nat Genet) Vol. 50 Issue 9 Pg. 1240-1246 (09 2018) ISSN: 1546-1718 [Electronic] United States
• PMID: 30127528 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• Transcription Factors

Topics

• Animals
• CRISPR-Cas Systems
• Cell Line, Tumor
• Disease Models, Animal
• Down-Regulation
• Female
• Gene Amplification
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, Nude
• N-Myc Proto-Oncogene Protein (genetics)
• Neuroblastoma (genetics)
• Transcription Factors (genetics)
• Transcription, Genetic