Advanced search
1 file | 4.70 MB

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

(2015) ONCOGENE. 34(26). p.3357-3368
Author
Organization
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.
Keywords
DIFFERENTIATION, TUMORS, PROGRESSION, P-TEFB, GENE-EXPRESSION, MIRNA EXPRESSION, SUBGROUPS, BIOLOGY, RISK STRATIFICATION, PHENOTYPE

Downloads

  • althoff et al 2015.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 4.70 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Althoff, Kristina, Anneleen Beckers, Emma Bell, Maike Nortmeyer, Theresa Thor, Annika Sprüssel, Sven Lindner, et al. 2015. “A Cre-conditional MYCN-driven Neuroblastoma Mouse Model as an Improved Tool for Preclinical Studies.” Oncogene 34 (26): 3357–3368.
APA
Althoff, K., Beckers, A., Bell, E., Nortmeyer, M., Thor, T., Sprüssel, A., Lindner, S., et al. (2015). A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies. ONCOGENE, 34(26), 3357–3368.
Vancouver
1.
Althoff K, Beckers A, Bell E, Nortmeyer M, Thor T, Sprüssel A, et al. A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies. ONCOGENE. 2015;34(26):3357–68.
MLA
Althoff, Kristina, Anneleen Beckers, Emma Bell, et al. “A Cre-conditional MYCN-driven Neuroblastoma Mouse Model as an Improved Tool for Preclinical Studies.” ONCOGENE 34.26 (2015): 3357–3368. Print.
@article{5706237,
  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 \ensuremath{\beta}-hydroxylase-expressing cells, termed LSL-MYCN;Dbh-iCre. These mice develop neuroblastic tumors with an incidence of {\textrangle}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.},
  author       = {Althoff, Kristina and Beckers, Anneleen and Bell, Emma and Nortmeyer, Maike and Thor, Theresa and Spr{\"u}ssel, Annika and Lindner, Sven and De Preter, Katleen and Florin, Alexandra and Heukamp, Lukas C and Klein-Hitpass, Ludger and Astrahantseff, Kathy and Kumps, Candy and Speleman, Franki and Eggert, Angelika and Westermann, Frank and Schramm, Alexander and Schulte, Johannes H},
  issn         = {0950-9232},
  journal      = {ONCOGENE},
  language     = {eng},
  number       = {26},
  pages        = {3357--3368},
  title        = {A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies},
  url          = {http://dx.doi.org/10.1038/onc.2014.269},
  volume       = {34},
  year         = {2015},
}

Altmetric
View in Altmetric
Web of Science
Times cited: