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,
Robert J. Spinner,
David A. Largaespada,
Nancy Ratner
Affiliations
Jianqiang Wu
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
Vincent W. Keng
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
Deanna M. Patmore
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
Jed J. Kendall
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
Ami V. Patel
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
Edwin Jousma
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
Walter J. Jessen
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
Kwangmin Choi
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
Barbara R. Tschida
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
Kevin A.T. Silverstein
Biostatistics and Informatics, University of Minnesota, Minneapolis, MN 55455, USA
Danhua Fan
Biostatistics and Informatics, University of Minnesota, Minneapolis, MN 55455, USA
Eric B. Schwartz
Ohio State University, College of Pharmacy, Columbus, OH 43210, USA
James R. Fuchs
Ohio State University, College of Pharmacy, Columbus, OH 43210, USA
Yuanshu Zou
Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Research Foundation, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
Mi-Ok Kim
Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Research Foundation, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
Eva Dombi
Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA
David E. Levy
Department of Pathology and New York University Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Gang Huang
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
Jose A. Cancelas
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
Anat O. Stemmer-Rachamimov
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
Robert J. Spinner
Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
David A. Largaespada
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
Nancy Ratner
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USA
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.
