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Other oncogenic mutations, such as amplification and increased expression of the <jats:italic>MYCN<\/jats:italic> gene, have been found even with proficient RB1 function. In this study, we investigated whether MYCN over-expression can drive carcinogenesis independently of <jats:italic>RB1<\/jats:italic> loss-of-function mutations. The aim was to elucidate the events that result in carcinogenesis and identify the cancer cell-of-origin. We used the chicken retina, a well-established model for studying retinal neurogenesis, and established human embryonic stem cell-derived retinal organoids as model systems. We over-expressed <jats:italic>MYCN<\/jats:italic> by electroporation of piggyBac genome-integrating expression vectors. We found that over-expression of MYCN induced tumorigenic growth with high frequency in RB1-proficient chicken retinas and human organoids. In both systems, the tumorigenic cells expressed markers for undifferentiated cone photoreceptor\/horizontal cell progenitors. The over-expression resulted in metastatic retinoblastoma within 7\u20139 weeks in chicken. Cells expressing MYCN could be grown in vitro and, when orthotopically injected, formed tumours that infiltrated the sclera and optic nerve and expressed markers for cone progenitors. Investigation of the tumour cell phenotype determined that the potential for neoplastic growth was embryonic stage-dependent and featured a cell-specific resistance to apoptosis in the cone\/horizontal cell lineage, but not in ganglion or amacrine cells. We conclude that MYCN over-expression is sufficient to drive tumorigenesis and that a cell-specific resistance to apoptosis in the cone\/horizontal cell lineage mediates the cancer phenotype.<\/jats:p>","DOI":"10.1038\/s41389-022-00409-3","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T05:03:56Z","timestamp":1655787836000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastoma"],"prefix":"10.1038","volume":"11","author":[{"given":"Maria K. 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