Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/60977
Title: Insertional mutagenesis identifies a STAT3/Arid1b/β-catenin pathway driving neurofibroma initiation
Authors: 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
Issue Date: 2016
Publisher: Cell Press
Source: Cell reports, 2016, v. 14, no. 8, p. 1979-1990 How to cite?
Journal: Cell reports 
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.
URI: http://hdl.handle.net/10397/60977
ISSN: 2211-1247
DOI: 10.1016/j.celrep.2016.01.074
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