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. 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; Michael A. Dyer

doi:10.1038/s41467-020-14682-6

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

Biostatistics

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71 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 language	English (US)
Article number	913
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14682-6
State	Published - Feb 14 2020

Bibliographical note

Funding 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).

Publisher Copyright:
© 2020, The Author(s).

Keywords

Animals
Child, Preschool
Cohort Studies
Female
Gene Amplification
Humans
Infant
Male
Mice
Mitochondria/genetics
Mutation
N-Myc Proto-Oncogene Protein/genetics
Neuroblastoma/genetics
Reactive Oxygen Species/metabolism
X-linked Nuclear Protein/genetics

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-14682-6

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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), Article 913. https://doi.org/10.1038/s41467-020-14682-6

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, MD, Kamiński, MM, Valentine, M, Pruett-Miller, SM, Pappo, A, Zhang, J, Clay, MR, Bahrami, A, Vogel, P, Lee, S, Shelat, A, Sarthy, JF, Meers, MP, George, RE, Mardis, ER, Wilson, RK, Henikoff, S, Downing, JR & Dyer, MA 2020, 'MYCN amplification and ATRX mutations are incompatible in neuroblastoma', Nature communications, vol. 11, no. 1, 913. https://doi.org/10.1038/s41467-020-14682-6

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title = "MYCN amplification and ATRX mutations are incompatible in neuroblastoma",

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.",

keywords = "Animals, Child, Preschool, Cohort Studies, Female, Gene Amplification, Humans, Infant, Male, Mice, Mitochondria/genetics, Mutation, N-Myc Proto-Oncogene Protein/genetics, Neuroblastoma/genetics, Reactive Oxygen Species/metabolism, X-linked Nuclear Protein/genetics",

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

note = "Funding 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{\textquoteright}s Lemonade Stand Foundation for Childhood Cancer, the Tully Family Foundation, and the Peterson Foundation. E.S. was supported by the St. Baldrick{\textquoteright}s Foundation. The statistical work was supported by NIH/NCI grant U10 CA180899 (Children{\textquoteright}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{\textquoteright}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). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = feb,

day = "14",

doi = "10.1038/s41467-020-14682-6",

language = "English (US)",

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T1 - MYCN amplification and ATRX mutations are incompatible in neuroblastoma

AU - Zeineldin, Maged

AU - Federico, Sara

AU - Chen, Xiang

AU - Fan, Yiping

AU - Xu, Beisi

AU - Stewart, Elizabeth

AU - Zhou, Xin

AU - Jeon, Jongrye

AU - Griffiths, Lyra

AU - Nguyen, Rosa

AU - Norrie, Jackie

AU - Easton, John

AU - Mulder, Heather

AU - Yergeau, Donald

AU - Liu, Yanling

AU - Wu, Jianrong

AU - Van Ryn, Collin

AU - Naranjo, Arlene

AU - Hogarty, Michael D.

AU - Kamiński, Marcin M.

AU - Valentine, Marc

AU - Pruett-Miller, Shondra M.

AU - Pappo, Alberto

AU - Zhang, Jinghui

AU - Clay, Michael R.

AU - Bahrami, Armita

AU - Vogel, Peter

AU - Lee, Seungjae

AU - Shelat, Anang

AU - Sarthy, Jay F.

AU - Meers, Michael P.

AU - George, Rani E.

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Henikoff, Steven

AU - Downing, James R.

AU - Dyer, Michael A.

N1 - Funding 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). Publisher Copyright: © 2020, The Author(s).

PY - 2020/2/14

Y1 - 2020/2/14

N2 - 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.

AB - 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.

KW - Animals

KW - Child, Preschool

KW - Cohort Studies

KW - Female

KW - Gene Amplification

KW - Humans

KW - Infant

KW - Male

KW - Mice

KW - Mitochondria/genetics

KW - Mutation

KW - N-Myc Proto-Oncogene Protein/genetics

KW - Neuroblastoma/genetics

KW - Reactive Oxygen Species/metabolism

KW - X-linked Nuclear Protein/genetics

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DO - 10.1038/s41467-020-14682-6

M3 - Article

C2 - 32060267

AN - SCOPUS:85079360040

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 913

ER -

MYCN amplification and ATRX mutations are incompatible in neuroblastoma

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Publisher link

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