Here, we show that MCPyV+ Merkel cell carcinoma is defined by neuroendocrine-lineage core regulatory (CR) transcription factors (TFs) (ATOH1, INSM1, ISL1, LHX3, POU4F3, and SOX2) that were essential for tumor survival and that co-bound chromatin with the viral small T antigen at super enhancers. This evidence concerns the gene ISL1 and Merkel cell skin cancer.