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.
Bibliographical noteFunding Information:
We thank Angie McArthur for editing the manuscript and Kevin Freeman for the MYCN-inducible constructs. The NBL-S cell line was provided by Garrett Brodeur. This work was supported, in part, by Cancer Center Support (CA21765) from the NCI, grants to M.A.D. from the NIH (EY014867, EY018599, and CA168875) and ALSAC. M.A.D. was also supported by a grant from Alex’s Lemonade Stand Foundation for Childhood Cancer, the Tully Family Foundation, and the Peterson Foundation. E.S. was supported by the St. Baldrick’s Foundation. The statistical work was supported by NIH/NCI grant U10 CA180899 (Children’s Oncology Group Statistics and Data Center). Most of this research was supported by the Howard Hughes Medical Institute. WGS, WGBS, and RNA-seq were performed as part of the St. Jude Children’s Research Hospital— Washington University PCGP. Preclinical studies were performed with assistance from the Animal Imaging Shared Resource; electron microscopy was performed with assistance from the Cell and Tissue Imaging Shared Resource; histopathologic analysis was performed with assistance from the Veterinary Pathology Shared Resource (all of St. Jude).
© 2020, The Author(s).