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 Ryn, Arlene Naranjo, Michael D. Hogarty, Marcin M. Kamiński, Marc 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 and Michael A. Dyer ()
Additional contact information
Maged Zeineldin: St. Jude Children’s Research Hospital
Sara Federico: St. Jude Children’s Research Hospital
Xiang Chen: St. Jude Children’s Research Hospital
Yiping Fan: St. Jude Children’s Research Hospital
Beisi Xu: St. Jude Children’s Research Hospital
Elizabeth Stewart: St. Jude Children’s Research Hospital
Xin Zhou: St. Jude Children’s Research Hospital
Jongrye Jeon: St. Jude Children’s Research Hospital
Lyra Griffiths: St. Jude Children’s Research Hospital
Rosa Nguyen: St. Jude Children’s Research Hospital
Jackie Norrie: St. Jude Children’s Research Hospital
John Easton: St. Jude Children’s Research Hospital
Heather Mulder: St. Jude Children’s Research Hospital
Donald Yergeau: St. Jude Children’s Research Hospital
Yanling Liu: St. Jude Children’s Research Hospital
Jianrong Wu: St. Jude Children’s Research Hospital
Collin Ryn: University of Florida
Arlene Naranjo: University of Florida
Michael D. Hogarty: Children’s Hospital of Philadelphia
Marcin M. Kamiński: St. Jude Children’s Research Hospital
Marc Valentine: St. Jude Children’s Research Hospital
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
Alberto Pappo: St. Jude Children’s Research Hospital
Jinghui Zhang: St. Jude Children’s Research Hospital
Michael R. Clay: St. Jude Children’s Research Hospital
Armita Bahrami: St. Jude Children’s Research Hospital
Peter Vogel: St. Jude Children’s Research Hospital
Seungjae Lee: St. Jude Children’s Research Hospital
Anang Shelat: Department of Chemical Biology and Therapeutics St. Jude Children’s Research Hospital
Jay F. Sarthy: Fred Hutchinson Cancer Research Center
Michael P. Meers: Fred Hutchinson Cancer Research Center
Rani E. George: Dana Farber Cancer Institute
Elaine R. Mardis: The Institute for Genomic Medicine, Nationwide Children’s Hospital
Richard K. Wilson: The Institute for Genomic Medicine, Nationwide Children’s Hospital
Steven Henikoff: Fred Hutchinson Cancer Research Center
James R. Downing: St. Jude Children’s Research Hospital
Michael A. Dyer: St. Jude Children’s Research Hospital

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14682-6

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