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 journalArticlepeer-review

51 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

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© 2016 The Authors.

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