MYCN amplification and ATRX mutations are incompatible in neuroblastoma

Maged Zeineldin, Sara Federico, Xiang Chen, Yiping Fan, Beisi Xu, Elizabeth Stewart, Xin Zhou, Jongrye Jeon, Lyra Griffiths, Rosa Nguyen, Jackie Norrie, John Easton, Heather Mulder, Donald Yergeau, Yanling Liu, Jianrong Wu, Collin Van Ryn, Arlene Naranjo, Michael D. Hogarty, Marcin M. KamińskiMarc Valentine, Shondra M. Pruett-Miller, Alberto Pappo, Jinghui Zhang, Michael R. Clay, Armita Bahrami, Peter Vogel, Seungjae Lee, Anang Shelat, Jay F. Sarthy, Michael P. Meers, Rani E. George, Elaine R. Mardis, Richard K. Wilson, Steven Henikoff, James R. Downing, Michael A. Dyer

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number913
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020
Externally publishedYes

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  • Cite this

    Zeineldin, M., Federico, S., Chen, X., Fan, Y., Xu, B., Stewart, E., Zhou, X., Jeon, J., Griffiths, L., Nguyen, R., Norrie, J., Easton, J., Mulder, H., Yergeau, D., Liu, Y., Wu, J., Van Ryn, C., Naranjo, A., Hogarty, M. D., ... Dyer, M. A. (2020). MYCN amplification and ATRX mutations are incompatible in neuroblastoma. Nature communications, 11(1), [913]. https://doi.org/10.1038/s41467-020-14682-6