MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma
Collin Van Ryn,
Michael D Hogarty,
Marcin M. Kamiński,
Shondra M. Pruett-Miller,
Michael R. Clay,
Rani E. George,
Elaine R. Mardis,
Richard K Wilson,
James R. Downing,
Michael A. Dyer,
for the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project
Posted 29 Jul 2018
bioRxiv DOI: 10.1101/379636 (published DOI: 10.1038/s41467-020-14682-6)
Posted 29 Jul 2018
Aggressive cancers often have activating mutations in growth controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA replicative stress. The combination of replicative stress caused by defects in the ATRX histone chaperone complex and that induced by MYCN mediated metabolic reprogramming leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high risk neuroblastoma.
- Downloaded 1,151 times
- Download rankings, all-time:
- Site-wide: 18,722
- In cancer biology: 436
- Year to date:
- Site-wide: 95,221
- Since beginning of last month:
- Site-wide: 106,184
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!