Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry
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 C...
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Published in | Nature genetics Vol. 50; no. 9; pp. 1240 - 1246 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.09.2018
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | These authors jointly supervised this work and represent co-principal investigators. These authors contributed equally to the study. |
ISSN: | 1061-4036 1546-1718 |
DOI: | 10.1038/s41588-018-0191-z |