Rxivist logo

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.

Download data

  • Downloaded 1,003 times
  • Download rankings, all-time:
    • Site-wide: 9,484 out of 78,238
    • In cancer biology: 269 out of 2,717
  • Year to date:
    • Site-wide: 25,993 out of 78,238
  • Since beginning of last month:
    • Site-wide: 62,322 out of 78,238

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News