Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggressive Murine Hepatoblastomas

Reconciling the Biological and Transcriptional Variability of Hepatoblastoma with Its Mutational Uniformity

“…Wang et al [48] recently investigated the role of the oxidant-responsive transcription factor NFE2L2/NRF2 (NFE2L2) in the pathogenesis of this large non-canonical subset of HBs. Again following a theme that recalls the regulation of β-catenin and YAP, NFE2L2 is normally maintained in an inactive cytoplasm complex with Kelch-like ECH-associated protein 1 (KEAP1), which mediates NFE2L2's rapid proteasome-mediated decay so as to ensure its low-level basal expression and transcriptional quiescence [49].…”

“…In response to oxidative or electrophilic stress, however, multiple KEAP1 cysteine residues are oxidized, causing the release, stabilization and nuclear translocation of NFE2L2, which, upon interacting with members of the small bZIP Maf family, alters the expression of several hundred target genes and mediates an anti-oxidant response [49][50][51]. An average of 4.6% of HBs, (range 0-9.8%) harbor missense mutations in one of NFE2L2's two KEAP1-interacting domains, which leads to NFE2L2's stabilization and nuclear localization even in the absence of any exogenous stress [19,48,[52][53][54]. Additionally, as many as 20% of certain adult epithelial neoplasms and 50% of HBs amplify the WT NFE2L2 gene at 2q32.1 and allow its encoded protein to stoichiometrically override the KEAP1 checkpoint [19,48,55,56].…”

Help for Sick Kids: New Insights Into Hepatoblastoma

“…To elucidate the role of NFE2L2/NRF2 mutations in the development of pediatric liver cancer, Prochownik’s group determined the effects of patient-derived NFE2L2/NRF2 mutants in the contest of β-catenin and YAP activation in transgenic mice. 6 These combinations reproduce the mutations that are typically observed in hepatoblastoma patients with chemoresistant, relapsed, and aggressive forms of the pediatric liver cancer. Remarkably, both patient-derived NFE2L2/NRF2 mutants significantly shortened survival of the mice in this setting, demonstrating a critical contribution of NFE2L2/NRF2 mutations to the aggressiveness of hepatoblastoma.…”

“…The authors did not stop here, but through transcriptomic analysis and functional follow-up identified the serine protease inhibitor serpin E1 to be responsible for extensive necrosis associated with NFE2L2/NRF2 mutations. Finally Wang et al 6 analyzed RNA-Seq data from 194 hepatoblastoma cases and found copy number variations and missense mutations in almost half of them, emphasizing the important role of NFE2L2/NRF2 mutations in aggressive hepatoblastoma. Thus, this elegant work showed the critical role of NFE2L2/NRF2 mutations in development of aggressive features of pediatric liver cancer including low survival rate, fast progression of tumors, and promotion of the widespread necrosis.…”

“…The study by Wang et al 6 provides a strong rationale for addressing mechanisms that contribute to the aggressiveness of hepatoblastoma. Particularly, 1 of the critical questions relates to the high levels of mutant β-catenin and NFE2L2/NRF2 proteins in patients with aggressive hepatoblastoma.…”