@article{ccf874f08f0f467583051e73a40128f6,
title = "Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation",
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.",
author = "Jianqiang Wu and Keng, {Vincent W.} and Patmore, {Deanna M.} and Kendall, {Jed J.} and Patel, {Ami V.} and Edwin Jousma and Jessen, {Walter J.} and Kwangmin Choi and Tschida, {Barbara R.} and Silverstein, {Kevin A.T.} and Danhua Fan and Schwartz, {Eric B.} and Fuchs, {James R.} and Yuanshu Zou and Kim, {Mi Ok} and Eva Dombi and Levy, {David E.} and Gang Huang and Cancelas, {Jose A.} and Stemmer-Rachamimov, {Anat O.} and Spinner, {Robert J.} and Largaespada, {David A.} and Nancy Ratner",
note = "Funding Information: We thank the Minnesota Supercomputing Institute for computational resources for sequence analysis, Dr. Ari Melnick (Weil Cornell Medical School) for assistance in design of histone modification analysis, and Ms. Huiqing Li for animal husbandry. This work was supported by NIH R01 NS28840 (N.R.), NIH P50 NS057531 (N.R. and D.A.L.), a DAMD New Investigator Award (W81XWH-11-1-0259), an Ohio State University Comprehensive Cancer Center Pelotonia Idea Grant (J.W.), and the American Cancer Society (IRG-67-003-44) (J.R.F.). The CHTN provided some benign neurofibromas used in this study. Funding Information: We thank the Minnesota Supercomputing Institute for computational resources for sequence analysis, Dr. Ari Melnick (Weil Cornell Medical School) for assistance in design of histone modification analysis, and Ms. Huiqing Li for animal husbandry. This work was supported by NIH R01 NS28840 (N.R.), NIH P50 NS057531 (N.R. and D.A.L.), a DAMD New Investigator Award (W81XWH-11-1-0259), an Ohio State University Comprehensive Cancer Center Pelotonia Idea Grant (J.W.), and the American Cancer Society (IRG-67-003-44) (J.R.F.). The CHTN provided some benign neurofibromas used in this study. Publisher Copyright: {\textcopyright} 2016 The Authors.",
year = "2016",
month = mar,
day = "1",
doi = "10.1016/j.celrep.2016.01.074",
language = "English (US)",
volume = "14",
pages = "1979--1990",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}