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-Rachamimov & 3 others Robert J. Spinner, David A. Largaespada, Nancy Ratner

Research output: Contribution to journalArticle

22 Citations (Scopus)

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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Catenins
Neurofibroma
Mutagenesis
Insertional Mutagenesis
Schwann Cells
Carcinogenesis
Histone Code
Genes
Cells
Neural Pathways
Wnt Signaling Pathway
Neurofibromatosis 1
Molecular Models
Epigenomics
Histones
Screening
Stem Cells
Transplantation
Testing

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wu, J., Keng, V. W., Patmore, D. M., Kendall, J. J., Patel, A. V., Jousma, E., ... 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

Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation. / Wu, Jianqiang; Keng, Vincent W.; Patmore, Deanna M.; Kendall, Jed J.; Patel, Ami V.; Jousma, Edwin; Jessen, Walter J.; Choi, Kwangmin; Tschida, Barbara R.; Silverstein, Kevin A.T.; Fan, Danhua; Schwartz, Eric B.; Fuchs, James R.; Zou, Yuanshu; Kim, Mi Ok; Dombi, Eva; Levy, David E.; Huang, Gang; Cancelas, Jose A.; Stemmer-Rachamimov, Anat O.; Spinner, Robert J.; Largaespada, David A.; Ratner, Nancy.

In: Cell Reports, Vol. 14, No. 8, 01.03.2016, p. 1979-1990.

Research output: Contribution to journalArticle

Wu, J, Keng, VW, Patmore, DM, Kendall, JJ, Patel, AV, Jousma, E, Jessen, WJ, Choi, K, Tschida, BR, Silverstein, KAT, Fan, D, Schwartz, EB, Fuchs, JR, Zou, Y, Kim, MO, Dombi, E, Levy, DE, Huang, G, Cancelas, JA, Stemmer-Rachamimov, AO, Spinner, RJ, Largaespada, DA & Ratner, N 2016, 'Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation', Cell Reports, vol. 14, no. 8, pp. 1979-1990. https://doi.org/10.1016/j.celrep.2016.01.074
Wu, Jianqiang ; Keng, Vincent W. ; Patmore, Deanna M. ; Kendall, Jed J. ; Patel, Ami V. ; Jousma, Edwin ; Jessen, Walter J. ; Choi, Kwangmin ; Tschida, Barbara R. ; Silverstein, Kevin A.T. ; Fan, Danhua ; Schwartz, Eric B. ; Fuchs, James R. ; Zou, Yuanshu ; Kim, Mi Ok ; Dombi, Eva ; Levy, David E. ; Huang, Gang ; Cancelas, Jose A. ; Stemmer-Rachamimov, Anat O. ; Spinner, Robert J. ; Largaespada, David A. ; Ratner, Nancy. / Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation. In: Cell Reports. 2016 ; Vol. 14, No. 8. pp. 1979-1990.
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AU - Patel, Ami V.

AU - Jousma, Edwin

AU - Jessen, Walter J.

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AU - Silverstein, Kevin A.T.

AU - Fan, Danhua

AU - Schwartz, Eric B.

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AU - Dombi, Eva

AU - Levy, David E.

AU - Huang, Gang

AU - Cancelas, Jose A.

AU - Stemmer-Rachamimov, Anat O.

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