Runx1/3-driven adaptive endoplasmic reticulum stress pathways contribute to neurofibromagenesis

Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2 alpha-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs.

Automated summary

Neurofibromatosis type 1 (NF1) patients are prone to develop plexiform neurofibromas (PNFs), and all three endoplasmic reticulum (ER) stress response pathways are activated in PNFs. Inhibition of protein kinase RNA [PKR]-like ER kinase (PERK) can reduce the number of neurofibroma-spheres and tumor-like lesions in mouse models. Deletion of PERK in Schwann cells (SCs) and Schwann cell precursors (SCPs) leads to reduced tumor size, number, and increased survival in a PNF mouse model. Targeting proteostasis could be a potential therapy for PNFs.