Epigenetic dysregulation is believed to be a major contributing factor in many cancers, including childhood neuroblastoma. This malignancy, which arises during embryonal development, is the most common tumour of infancy and results from the aberrant persistence of neural crest progenitors during sympathetic nervous system development. Children with aggressive undifferentiated neuroblastomas frequently display amplification of MYCN, which confers a particular poor outcome. Th-MYCN transgenic mice with targeted expression of human MYCN to neural crest cells, develop neuroblastoma that closely recapitulates the human disease with respect to major molecular, biologic and cytogenetic features. We performed a large-scale in vivo N-ethyl-N-nitrosurea (ENU) mutagenesis screen on these mice and from this established a founder line displaying heritable loss of tumour formation. Mapping studies identified a single point mutation in the transcriptional corepressor Runx1t1 that was responsible for the loss of tumour phenotype observed. The mutation causes complete disruption of a highly conserved zinc finger domain within Runx1t1. A second mouse model with targeted disruption of Runx1t1 demonstrated that Runx1t1 haploinsufficiency is sufficient to prevent neuroblastoma development, while wild type mice remain completely healthy and fertile despite having only one functional copy of Runx1t1. Results will be presented showing that Runx1t1 forms part of a transcriptional co-repressor complex that regulates the epigenomic landscape as well as chromatin accessibility in neuroblastoma, to control cell fate pathway genes and maintain a de-differentiated state.