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Runx1 contributes to neurofibromatosis type 1 neurofibroma formation

Oncogene volume 35, pages 1468–1474 (2016)Cite this article

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Abstract

Neurofibromatosis type 1 (NF1) patients are predisposed to neurofibromas but the driver(s) that contribute to neurofibroma formation are not fully understood. By cross comparison of microarray gene lists on human neurofibroma-initiating cells and developed neurofibroma Schwann cells (SCs) we identified RUNX1 overexpression in human neurofibroma initiation cells, suggesting RUNX1 might relate to neurofibroma formation. Immunostaining confirmed RUNX1 protein overexpression in human plexiform neurofibromas. Runx1 overexpression was confirmed in mouse Schwann cell progenitors (SCPs) and mouse neurofibromas at the messenger RNA and protein levels. Genetic inhibition of Runx1 expression by small hairpin RNA or pharmacological inhibition of Runx1 function by a Runx1/Cbfβ interaction inhibitor, Ro5-3335, decreased mouse neurofibroma sphere number in vitro. Targeted genetic deletion of Runx1 in SCs and SCPs delayed mouse neurofibroma formation in vivo. Mechanistically, loss of Nf1 increased embryonic day 12.5 Runx1+/Blbp+ progenitors that enable tumor formation. These results suggest that Runx1 has an important role in Nf1 neurofibroma initiation, and inhibition of RUNX1 function might provide a novel potential therapeutic treatment strategy for neurofibroma patients.

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Acknowledgements

We thank Dr Nancy Ratner for providing the microarray data (supported by NS28840 to NR) and critical review and helpful discussions of the manuscript. This work was supported by a Cincinnati Children’s Hospital Trustee Grant to JW.

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Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Research Foundation, Cincinnati Children’s Hospital, University of Cincinnati, Cincinnati, OH, USA,

    H Li, X Zhao, X Yan, W J Jessen, G Huang & J Wu

  2. Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Research Foundation, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH, USA

    M-O Kim

  3. Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA

    E Dombi

  4. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    P P Liu

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  1. H Li
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Correspondence to J Wu.

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Li, H., Zhao, X., Yan, X. et al. Runx1 contributes to neurofibromatosis type 1 neurofibroma formation. Oncogene 35, 1468–1474 (2016). https://doi.org/10.1038/onc.2015.207

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