biostudies-literatureUnknownQadeer ZANCI NIH HHSNIH HHSMedulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 MB (G3MB) has poor overall survival at <50%, high frequencies of metastases, and no targeted therapies. Amplification of <i>MYC</i> and activation of TGFβ signaling occur frequently in G3MB. Many tumors have no reported mutations, suggesting epigenetic drivers. We here describe novel humanized models for G3MB from human induced pluripotent stem cells (hiPSC). By transducing hiPSC-derived neuroepithelial stem cells (NESC), we determined that: 1) both MYC and TGFβ effectors drove tumors <i>in vivo</i>; 2) MYC/TGFβR1 in combination led to more aggressive tumors and resistance to clinical inhibitors of TGFβ, and 3) NESC-derived tbioRxiv : the preprint server for biology2025.12.06.689939https://www.ebi.ac.uk/biostudies/studies/S-EPMC12709477biostudies-literatureHuman stem cell models for group 3 medulloblastoma uncover JARID1B as a regulator of the chromatin landscape.PMC12709477P50 CA097257P30 CA082103S10 OD028511T32 CA151022Taylor MDJohnson MOGrele SPhua RNorthcott PAGuney ESiegel DHuang MIsmael WMHendrikse LQadeer ZASmith KWang LGaspar-Maia AWestelman SHou EGudenas BWeiss WAfalseHuman stem cell models for group 3 medulloblastoma uncover JARID1B as a regulator of the chromatin landscape.Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 MB (G3MB) has poor overall survival at <50%, high frequencies of metastases, and no targeted therapies. Amplification of <i>MYC</i> and activation of TGFβ signaling occur frequently in G3MB. Many tumors have no reported mutations, suggesting epigenetic drivers. We here describe novel humanized models for G3MB from human induced pluripotent stem cells (hiPSC). By transducing hiPSC-derived neuroepithelial stem cells (NESC), we determined that: 1) both MYC and TGFβ effectors drove tumors <i>in vivo</i>; 2) MYC/TGFβR1 in combination led to more aggressive tumors and resistance to clinical inhibitors of TGFβ, and 3) NESC-derived t2025-01-01T00:00:00Z2025 Dec2026-07-05T03:12:17.533Z2026-07-05T03:08:27.103ZS-EPMC127094774141538010.64898/2025.12.06.689939