Novel MYC-driven medulloblastoma models generated by CRISPR activation of endogenous Myc

Myc-driven Group 3 medulloblastoma (MB) is the most aggressive tumor among the four subgroups classified by transcriptome, genomic landscape and clinical outcomes. So far in all available mouse Group 3 models, the constitutive ectopic Myc expression was under control of LTR element or other exogenous promoters within the vectors, which were randomly inserted into the genome with multiple copies. Here we are deploying nuclease deficient CRISPR/dCas9-based transactivator that is targeted to promoter DNA sequences by specific guide RNA to force the transcriptional activation of endogenous Myc in p53-/-;cdkn2c-/- neurospheres cells. A combination of three sgRNAs together with dCas9-VP64 induced the highest expression of endogenous Myc. When the targeted cells were transplanted to the cortex of recipients, tumors arose fully recapitulate the Group 3 MB in human. This novel mouse model should significantly strengthen our understanding and treatment of the Myc-driven Group 3 medulloblastoma.

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Vo BT, Kwon JA, Li C, Finkelstein D, Xu B, Orr BA, Sherr CJ, Roussel MF