MYCN amplification and ATRX mutations are incompatible in neuroblastoma

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

doi:10.1038/s41467-020-14682-6

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.

Highlights

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes
Higher ATRX-mutation frequencies are detected in patients with International Neuroblastoma Staging System (INSS) stage 4 disease (8.6%), high-risk subgroup (14.6%), 11q loss of heterozygosity (LOH), or unfavorable histology and in INSS stage Risk Group Sex MYCN (FISH) MYCN (NGS) ALK Ploidy 11q LOH 1p LOH Histology Age at diagnosis Age at diagnosis
We show that amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene are mutually exclusive in neuroblastomas from patients of all ages and stages of disease

Summary

Introduction

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. Amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. ATRX and MYCN represent an unusual example, where inactivation of a tumorsuppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high-risk neuroblastoma. In cells lacking ATRX, H3.3 is not efficiently deposited at the telomeric G-rich regions, G4 structures form, and replication forks stall[4,5]. The formation of G4 structures in other G-rich repetitive regions of the genome can cause replicative stress[7,8] or block transcription[9]. In ATRXdeficient cells, PRC2-mediated modification of H3 to H3K27me[3] lacks specificity, and genes that are normally repressed by polycomb are deregulated[10]

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