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Oncogene. 2015 Jun;34(26):3357-68. doi: 10.1038/onc.2014.269. Epub 2014 Sep 1.

A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies.

Author information

1
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.
2
Center for Medical Genetics Ghent (CMGG), Ghent University Hospital, De Pintelaan 185, Ghent, Belgium.
3
German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
4
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.
5
Institute of Pathology, University Hospital Cologne, Cologne, Germany.
6
1] Institute of Pathology, University Hospital Cologne, Cologne, Germany [2] New Oncology -a division of Blackfield AG, Köln, Germany.
7
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
8
Department of Pediatric Oncology, Hematology and BMT, Charité University Medicine, Augustenburger Platz 1, Berlin, Germany.
9
Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany.
10
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.

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.

PMID:
25174395
PMCID:
PMC4487199
DOI:
10.1038/onc.2014.269
[Indexed for MEDLINE]
Free PMC Article

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