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

Publication ,  Journal Article
Zhukova, N; Ramaswamy, V; Remke, M; Martin, DC; Castelo-Branco, P; Zhang, CH; Fraser, M; Tse, K; Poon, R; Shih, DJH; Baskin, B; Ray, PN ...
Published in: Acta Neuropathol Commun
December 24, 2014

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.

Duke Scholars

Published In

Acta Neuropathol Commun

DOI

EISSN

2051-5960

Publication Date

December 24, 2014

Volume

2

Start / End Page

174

Location

England

Related Subject Headings

  • beta Catenin
  • Young Adult
  • Wnt Signaling Pathway
  • Wnt Proteins
  • Tumor Suppressor Protein p53
  • Radiotherapy
  • Neoplastic Stem Cells
  • Mutation
  • Medulloblastoma
  • Male
 

Citation

APA
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ICMJE
MLA
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Zhukova, N., Ramaswamy, V., Remke, M., Martin, D. C., Castelo-Branco, P., Zhang, C. H., … Tabori, U. (2014). WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma. Acta Neuropathol Commun, 2, 174. https://doi.org/10.1186/s40478-014-0174-y
Zhukova, Nataliya, Vijay Ramaswamy, Marc Remke, Dianna C. Martin, Pedro Castelo-Branco, Cindy H. Zhang, Michael Fraser, et al. “WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma.Acta Neuropathol Commun 2 (December 24, 2014): 174. https://doi.org/10.1186/s40478-014-0174-y.
Zhukova N, Ramaswamy V, Remke M, Martin DC, Castelo-Branco P, Zhang CH, et al. WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma. Acta Neuropathol Commun. 2014 Dec 24;2:174.
Zhukova, Nataliya, et al. “WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma.Acta Neuropathol Commun, vol. 2, Dec. 2014, p. 174. Pubmed, doi:10.1186/s40478-014-0174-y.
Zhukova N, Ramaswamy V, Remke M, Martin DC, Castelo-Branco P, Zhang CH, Fraser M, Tse K, Poon R, Shih DJH, Baskin B, Ray PN, Bouffet E, Dirks P, von Bueren AO, Pfaff E, Korshunov A, Jones DTW, Northcott PA, Kool M, Pugh TJ, Pomeroy SL, Cho Y-J, Pietsch T, Gessi M, Rutkowski S, Bognár L, Cho B-K, Eberhart CG, Conter CF, Fouladi M, French PJ, Grajkowska WA, Gupta N, Hauser P, Jabado N, Vasiljevic A, Jung S, Kim S-K, Klekner A, Kumabe T, Lach B, Leonard JR, Liau LM, Massimi L, Pollack IF, Ra YS, Rubin JB, Van Meir EG, Wang K-C, Weiss WA, Zitterbart K, Bristow RG, Alman B, Hawkins CE, Malkin D, Clifford SC, Pfister SM, Taylor MD, Tabori U. WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma. Acta Neuropathol Commun. 2014 Dec 24;2:174.
Journal cover image

Published In

Acta Neuropathol Commun

DOI

EISSN

2051-5960

Publication Date

December 24, 2014

Volume

2

Start / End Page

174

Location

England

Related Subject Headings

  • beta Catenin
  • Young Adult
  • Wnt Signaling Pathway
  • Wnt Proteins
  • Tumor Suppressor Protein p53
  • Radiotherapy
  • Neoplastic Stem Cells
  • Mutation
  • Medulloblastoma
  • Male