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MYCN amplification and ATRX mutations are incompatible in neuroblastoma.
Nature Communications ( IF 16.6 ) Pub Date : 2020-02-14 , DOI: 10.1038/s41467-020-14682-6
Maged Zeineldin 1 , Sara Federico 2 , Xiang Chen 3, 4 , Yiping Fan 3 , Beisi Xu 3 , Elizabeth Stewart 2 , Xin Zhou 3 , Jongrye Jeon 1 , Lyra Griffiths 1 , Rosa Nguyen 1 , Jackie Norrie 1 , John Easton 3 , Heather Mulder 3 , Donald Yergeau 3 , Yanling Liu 3 , Jianrong Wu 5 , Collin Van Ryn 6 , Arlene Naranjo 6 , Michael D Hogarty 7 , Marcin M Kamiński 8 , Marc Valentine 9 , Shondra M Pruett-Miller 10 , Alberto Pappo 2 , Jinghui Zhang 3 , Michael R Clay 11 , Armita Bahrami 11 , Peter Vogel 11 , Seungjae Lee 11 , Anang Shelat 12 , Jay F Sarthy 13 , Michael P Meers 13 , Rani E George 14 , Elaine R Mardis 15 , Richard K Wilson 15 , Steven Henikoff 13, 16 , James R Downing 11 , Michael A Dyer 1, 4, 16, 17
Affiliation  

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.

中文翻译:

MYCN扩增和ATRX突变在神经母细胞瘤中不相容。

侵略性癌症通常在控制生长的癌基因中具有激活突变,而在肿瘤抑制基因中具有失活突变。在神经母细胞瘤中,MYCN癌基因的扩增和ATRX肿瘤抑制基因的失活与高危疾病和不良预后相关。在这里,我们显示ATRX突变和MYCN扩增在成神经细胞瘤的各个年龄段和所有阶段都是互斥的。使用人类细胞系和小鼠模型,我们发现升高的MYCN表达和ATRX突变是不相容的。MYCN水平升高会促进代谢重编程,线粒体功能障碍,活性氧种类生成和DNA复制应激。由ATRX-组蛋白伴侣复合物缺陷引起的复制应激与MYCN介导的代谢重编程所引起的复制应激相结合,导致合成杀伤力。因此,ATRX和MYCN代表了一个不寻常的例子,其中抑癌基因的失活和癌基因的活化是不相容的。这种合成的杀伤力最终可用于改善高危神经母细胞瘤患者的预后。
更新日期:2020-02-14
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