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

Oncogene volume 42, pages 1038–1047 (2023)Cite this article

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Abstract

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-eIF2α-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.

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Fig. 1: ER stress-related genes are up-regulated in both human and mouse plexiform neurofibromas (PNFs).
Fig. 2: PERK expression is increased in mouse and human PNFs and appears to be partially MEK/ERK and RUNX- dependent.
Fig. 3: PERK inhibition affects Schwann cell precursor growth or tumorigenesis.
Fig. 4: Genetic deletion of PERK prolongs survival time and decreases tumor number and size in the Nf1fl/fl;DhhCre PNF mouse.
Fig. 5: Total p21 and cytoplasmic p21 expressions are increased in mouse and human PNFs.
Fig. 6: Exportin-1 regulates p21 translocation from nucleus to cytoplasm.
Fig. 7: Runx relates UPRs and protein synthesis in mouse neurofibromas with the regulation of ribosomal gene functions.

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Acknowledgements

We thank Ms Bethany Bresnen for editing the figures. We also thank Mr Jonathan Rose for performing genotyping on some mice. This work was supported by NIH R01 NS097233 to JW and R01NS28840 to NR.

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Author notes

  1. Yanan Yu

    Present address: College of Life Science, Xuzhou Medical University, 221004, Jiangsu, P. R. China

Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA

    Youjin Na, Ashley Hall, Yanan Yu, Liang Hu, Kwangmin Choi, Jake A. Burgard, Nancy Ratner & Jianqiang Wu

  2. Department of Pediatrics and Department of Pediatric Pathology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA

    Sara Szabo

  3. Department of Cell Systems & Anatomy and Department of Pathology & Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, TX, USA

    Gang Huang

  4. Department of Pathology & Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, TX, 78229, USA

    Gang Huang

  5. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA

    Nancy Ratner & Jianqiang Wu

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Contributions

GH, NR, and JW designed analyses, and discussed results. YN, AH, YY, LH and JAB performed experiments. KC performed bioinformatic analysis. SS reviewed the slides. YN, GH, NR, and JW wrote and edited the paper.

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Correspondence to Jianqiang Wu.

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Na, Y., Hall, A., Yu, Y. et al. Runx1/3-driven adaptive endoplasmic reticulum stress pathways contribute to neurofibromagenesis. Oncogene 42, 1038–1047 (2023). https://doi.org/10.1038/s41388-023-02620-x

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