Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

Jianqiang Wu, Vincent W. Keng, Deanna M. Patmore, Jed J. Kendall, Ami V. Patel, Edwin Jousma, Walter J. Jessen, Kwangmin Choi, Barbara R. Tschida, Kevin A.T. Silverstein, Danhua Fan, Eric B. Schwartz, James R. Fuchs, Yuanshu Zou, Mi Ok Kim, Eva Dombi, David E. Levy, Gang Huang, Jose A. Cancelas, Anat O. Stemmer-RachamimovRobert J. Spinner, David A. Largaespada, Nancy Ratner

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1) neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/β-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and β-catenin activity. β-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and β-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3β and the SWI/SNF gene Arid1b to increase β-catenin. Knockdown of Arid1b or Gsk3β in Stat3fl/fl;Nf1fl/fl;DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1-dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway and support testing JAK/STAT and Wnt/β-catenin pathway inhibitors in neurofibroma therapeutic trials.

Original languageEnglish (US)
Pages (from-to)1979-1990
Number of pages12
JournalCell reports
Volume14
Issue number8
DOIs
StatePublished - Mar 1 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wu, J., Keng, V. W., Patmore, D. M., Kendall, J. J., Patel, A. V., Jousma, E., Jessen, W. J., Choi, K., Tschida, B. R., Silverstein, K. A. T., Fan, D., Schwartz, E. B., Fuchs, J. R., Zou, Y., Kim, M. O., Dombi, E., Levy, D. E., Huang, G., Cancelas, J. A., ... Ratner, N. (2016). Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation. Cell reports, 14(8), 1979-1990. https://doi.org/10.1016/j.celrep.2016.01.074