You are here

Nat Genet DOI:10.1038/s41588-018-0191-z

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

Publication TypeJournal Article
Year of Publication2018
AuthorsDurbin, AD, Zimmerman, MW, Dharia, NV, Abraham, BJ, Iniguez, ABalboni, Weichert-Leahey, N, He, S, Krill-Burger, JM, Root, DE, Vazquez, F, Tsherniak, A, Hahn, WC, Golub, TR, Young, RA, A Look, T, Stegmaier, K
JournalNat Genet
Volume50
Issue9
Pages1240-1246
Date Published2018 09
ISSN1546-1718
KeywordsAnimals, Cell Line, Tumor, CRISPR-Cas Systems, Disease Models, Animal, Down-Regulation, Female, Gene Amplification, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Nude, N-Myc Proto-Oncogene Protein, Neuroblastoma, Transcription Factors, Transcription, Genetic
Abstract

Childhood high-risk neuroblastomas with MYCN gene amplification are difficult to treat effectively. 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, 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.

DOI10.1038/s41588-018-0191-z
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/30127528?dopt=Abstract

Alternate JournalNat Genet
PubMed ID30127528
PubMed Central IDPMC6386470
Grant ListR01 GM123511 / GM / NIGMS NIH HHS / United States
T32 CA136432 / CA / NCI NIH HHS / United States
R35 CA210030 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
R35 CA210064 / CA / NCI NIH HHS / United States
/ HHMI_ / Howard Hughes Medical Institute / United States
R01 CA180692 / CA / NCI NIH HHS / United States
R01 NS088355 / NS / NINDS NIH HHS / United States