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TP53  mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates  TP53  related radioresistance and can be used to sensitize  TP53  mutant tumors for radiation. We examined the subgroup-specific role of  TP53  mutations in a cohort of 314 patients treated with radiation.  TP53  wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of  TP53  mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/ TP53  mutant medulloblastoma had higher 5-year survival than those with SHH/ TP53  mutant tumours (100% and 36.6% ± 8.7%, respectively (p < 0.001)). Introduction of  TP53  mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% ± 2% vs. 57.4% ± 1.8% (p < 0.01)). In contrast, β-catenin mutation sensitized  TP53  mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized  TP53  mutant medulloblastoma to radiation (SF2 of 43.5% ± 1.5% in lithium treated cells vs. 56.6 ± 3% (p < 0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% ± 8% for lithium treated cells vs. 27% ± 3% for untreated controls (p = 0.05). Poor survival of patients with  TP53  mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes  TP53  mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.   Electronic supplementary material  The online version of this article (doi:10.1186/s40478-014-0174-y) contains supplementary material, which is available to authorized users.

WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma