WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
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Author
Zhukova, Nataliya
Ramaswamy, Vijay
Remke, Marc
Martin, Dianna C
Castelo-Branco, Pedro
Zhang, Cindy H
Fraser, Michael
Tse, Ken
Poon, Raymond
Shih, David JH
Baskin, Berivan
Ray, Peter N
Bouffet, Eric
Dirks, Peter
von Bueren, Andre O
Pfaff, Elke
Korshunov, Andrey
Jones, David TW
Northcott, Paul A
Kool, Marcel
Pugh, Trevor J
Cho, Yoon-Jae
Pietsch, Torsten
Gessi, Marco
Rutkowski, Stefan
Bognár, Laszlo
Cho, Byung-Kyu
Eberhart, Charles G
Conter, Cecile Faure
Fouladi, Maryam
French, Pim J
Grajkowska, Wieslawa A
Gupta, Nalin
Hauser, Peter
Jabado, Nada
Vasiljevic, Alexandre
Jung, Shin
Kim, Seung-Ki
Klekner, Almos
Kumabe, Toshihiro
Lach, Boleslaw
Leonard, Jeffrey R
Liau, Linda M
Massimi, Luca
Pollack, Ian F
Ra, Young Shin
Rubin, Joshua B
Van Meir, Erwin G
Wang, Kyu-Chang
Weiss, William A
Zitterbart, Karel
Bristow, Robert G
Alman, Benjamin
Hawkins, Cynthia E
Malkin, David
Clifford, Steven C
Pfister, Stefan M
Taylor, Michael D
Tabori, Uri
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1186/s40478-014-0174-yMetadata
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Zhukova, N., V. Ramaswamy, M. Remke, D. C. Martin, P. Castelo-Branco, C. H. Zhang, M. Fraser, et al. 2014. “WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma.” Acta Neuropathologica Communications 2 (1): 174. doi:10.1186/s40478-014-0174-y. http://dx.doi.org/10.1186/s40478-014-0174-y.Abstract
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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297452/pdf/Terms of Use
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