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Background  High-intensity therapy effectively treats most  TP53  wild-type ( TP53 -WT) Sonic Hedgehog-subgroup medulloblastomas (SHH-MBs), but often cause long-term deleterious neurotoxicities in children. Recent clinical trials investigating reduction/de-escalation of therapy for  TP53 -WT SHH-MBs caused poor overall survival. Here, we investigated whether reduced levels of p53-pathway activation by low-intensity therapy potentially contribute to diminished therapeutic efficacy.    Methods  Using mouse SHH-MB models with different p53 activities, we investigated therapeutic efficacy by activating p53-mediated cell-cycle arrest versus p53-mediated apoptosis on radiation-induced recurrence.    Results  Upon radiation treatment, p53 WT -mediated apoptosis was sufficient to eliminate all SHH-MB cells, including Sox2 +  cells. The same treatment eliminated most Sox2 −  bulk tumor cells in SHH-MBs harboring  p53  R172P , an apoptosis-defective allele with cell-cycle arrest activity, via inducing robust neuronal differentiation. Rare quiescent Sox2 +  cells survived radiation-enhanced p53 R172P  activation and entered a proliferative state, regenerating tumors. Transcriptomes of Sox2 +  cells resembled quiescent Nestin-expressing progenitors in the developing cerebellum, expressing Olig2 known to suppress p53 and p21 expression. Importantly, high  SOX2  expression is associated with poor survival of all four SHH-MB subgroups, independent of  TP53  mutational status.    Conclusions  Quiescent Sox2 +  cells are efficiently eliminated by p53-mediated apoptosis, but not cell-cycle arrest and differentiation. Their survival contributes to tumor recurrence due to insufficient p53-pathway activation.

Sox2+ cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence