SRP124716 PRJNA417797 GSE106725 MYCN Drives Disparate Medulloblastoma from Human Embryonic and iPSC-Derived Stem Cells [seq] How tumors develop or respond to therapies vary significantly among species. Here we report that medulloblastoma (MB) the most frequent malignant childhood brain tumor can develop from human hindbrain neuro-epithelial stem (hbNES) cells or induced pluripotent stem cell (iPSC)-derived NES (NES) cells via MYCN overexpression in mice. NES tumors developed fast with leptomeningeal dissemination, while hbNES tumors formed significantly later with no dissemination. By using large cohorts of MB patients we show that tumors resemble a common subgroup of Sonic Hedgehog (SHH) MBs and that pluripotency and mTOR signaling correlate with poor prognosis. To conclude, both iPSC-derived and embryonic NES cells can be transformed into distinct humanized MB models valuable for identifying better diagnostic markers and drug targets. Overall design: In total 75 samples were profiled for RNA expression; 7 embryonic and iPS-derived stem cell lines, 1 pre-tumor cell line, 37 snap frozen tumor model biopsies, 10 tumor model derived cell lines, 20 PDX tumor biopsies. Total 16 samples were profiled for DNA methylation; 6 embryonic and iPS-derived stem cell lines, 3 snap frozen tumor model biopsies, 6 tumor model derived cell lines GSE106725 pubmed 31786016 parent_bioproject PRJNA417799