title: A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies.
abstract: Neuroblastoma, a childhood cancer that originates from neural crest-derived cells, is the most common deadly solid tumor of infancy. Amplification of the MYCN oncogene, which occurs in approximately 20-25% of human neuroblastomas, is the most prominent genetic marker of high-stage disease. The availability of valid preclinical in vivo models is a prerequisite to develop novel targeted therapies. We here report on the generation of transgenic mice with Cre-conditional induction of MYCN in dopamine β-hydroxylase-expressing cells, termed LSL-MYCN;Dbh-iCre. These mice develop neuroblastic tumors with an incidence of >75%, regardless of strain background. Molecular profiling of tumors revealed upregulation of the MYCN-dependent miR-17-92 cluster as well as expression of neuroblastoma marker genes, including tyrosine hydroxylase and the neural cell adhesion molecule 1. Gene set enrichment analyses demonstrated significant correlation with MYC-associated expression patterns. Array comparative genome hybridization showed that chromosomal aberrations in LSL-MYCN;Dbh-iCre tumors were syntenic to those observed in human neuroblastomas. Treatment of a cell line established from a tumor derived from a LSL-MYCN;Dbh-iCre mouse with JQ1 or MLN8237 reduced cell viability and demonstrated oncogene addiction to MYCN. Here we report establishment of the first Cre-conditional human MYCN-driven mouse model for neuroblastoma that closely recapitulates the human disease with respect to tumor localization, histology, marker expression and genomic make up. This mouse model is a valuable tool for further functional studies and to assess the effect of targeted therapies.
authors.affiliation: 1] Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany [2] German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Hufelandstr, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Althoff
authors.affiliation: Center for Medical Genetics Ghent (CMGG), Ghent University Hospital, De Pintelaan 185, Ghent, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Beckers
authors.affiliation: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Bell
authors.affiliation: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Nortmeyer
authors.affiliation: 1] Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany [2] German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Hufelandstr, Germany [3] German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany [4] Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Thor
authors.affiliation: 1] Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany [2] German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Hufelandstr, Germany [3] German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany [4] Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sprüssel
authors.affiliation: 1] Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany [2] German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Hufelandstr, Germany [3] German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany [4] Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lindner
authors.affiliation: Center for Medical Genetics Ghent (CMGG), Ghent University Hospital, De Pintelaan 185, Ghent, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: De Preter
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Florin
authors.affiliation: 1] Institute of Pathology, University Hospital Cologne, Cologne, Germany [2] New Oncology -a division of Blackfield AG, Köln, Germany.
authors.forename: L C
authors.initials: LC
authors.lastname: Heukamp
authors.affiliation: Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Klein-Hitpass
authors.affiliation: Department of Pediatric Oncology, Hematology and BMT, Charité University Medicine, Augustenburger Platz 1, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Astrahantseff
authors.affiliation: Center for Medical Genetics Ghent (CMGG), Ghent University Hospital, De Pintelaan 185, Ghent, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Kumps
authors.affiliation: Center for Medical Genetics Ghent (CMGG), Ghent University Hospital, De Pintelaan 185, Ghent, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Department of Pediatric Oncology, Hematology and BMT, Charité University Medicine, Augustenburger Platz 1, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Eggert
authors.affiliation: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Westermann
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schramm
authors.affiliation: 1] Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany [2] German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Hufelandstr, Germany [3] Center for Medical Genetics Ghent (CMGG), Ghent University Hospital, De Pintelaan 185, Ghent, Belgium [4] German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany [5] Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: J H
authors.initials: JH
authors.lastname: Schulte
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D019426:Integrases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D046228:Microarray Analysis; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D019076:Transgenes; D014407:Tumor Cells, Cultured
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C045073:Cre recombinase; D019426:Integrases