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 Stat3(fl/fl);Nf1(fl/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.

• Authors: 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, Robert J Spinner, David A Largaespada, Nancy Ratner
• Journal: Cell reports (Cell Rep) Vol. 14 Issue 8 Pg. 1979-90 (Mar 01 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 26904939 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• CTNNB1 protein, mouse
• DNA-Binding Proteins
• Histones
• Neurofibromin 1
• Nuclear Proteins
• RNA, Small Interfering
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Transcription Factors
• beta Catenin
• N-Terminal Acetyltransferase A
• Naa11 protein, mouse
• Glycogen Synthase Kinase 3 beta
• Smarca4 protein, mouse
• DNA Helicases

Topics

• Animals
• Carcinogenesis (genetics, metabolism, pathology)
• DNA Helicases (genetics, metabolism)
• DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• Disease Models, Animal
• Female
• Gene Expression Regulation, Neoplastic
• Glycogen Synthase Kinase 3 beta (antagonists & inhibitors, genetics, metabolism)
• Histones (genetics, metabolism)
• Humans
• Mice
• Mice, Nude
• Mutagenesis, Insertional
• N-Terminal Acetyltransferase A (antagonists & inhibitors, genetics, metabolism)
• Neoplasm Transplantation
• Neural Stem Cells (metabolism, pathology)
• Neurofibromatosis 1 (genetics, metabolism, pathology)
• Neurofibromin 1 (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Peripheral Nervous System Neoplasms (genetics, metabolism, pathology)
• Phosphorylation
• RNA, Small Interfering (genetics, metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Schwann Cells (metabolism, pathology)
• Signal Transduction
• Transcription Factors (genetics, metabolism)
• beta Catenin (genetics, metabolism)