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

TY - JOUR

T1 - WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

AU - Zhukova, Nataliya

AU - Ramaswamy, Vijay

AU - Remke, Marc

AU - Martin, Dianna C

AU - Castelo-Branco, Pedro

AU - Zhang, Cindy H

AU - Fraser, Michael

AU - Tse, Ken

AU - Poon, Raymond

AU - Shih, David J H

AU - Baskin, Berivan

AU - Ray, Peter N

AU - Bouffet, Eric

AU - Dirks, Peter

AU - von Bueren, Andre O

AU - Pfaff, Elke

AU - Korshunov, Andrey

AU - Jones, David T W

AU - Northcott, Paul A

AU - Kool, Marcel

AU - Pugh, Trevor J

AU - Pomeroy, Scott L

AU - Cho, Yoon-Jae

AU - Pietsch, Torsten

AU - Gessi, Marco

AU - Rutkowski, Stefan

AU - Bognár, Laszlo

AU - Cho, Byung-Kyu

AU - Eberhart, Charles G

AU - Conter, Cecile Faure

AU - Fouladi, Maryam

AU - French, Pim J

AU - Grajkowska, Wieslawa A

AU - Gupta, Nalin

AU - Hauser, Peter

AU - Jabado, Nada

AU - Vasiljevic, Alexandre

AU - Jung, Shin

AU - Kim, Seung-Ki

AU - Klekner, Almos

AU - Kumabe, Toshihiro

AU - Lach, Boleslaw

AU - Leonard, Jeffrey R

AU - Liau, Linda M

AU - Massimi, Luca

AU - Pollack, Ian F

AU - Ra, Young Shin

AU - Rubin, Joshua B

AU - Van Meir, Erwin G

AU - Wang, Kyu-Chang

AU - Weiss, William A

AU - Zitterbart, Karel

AU - Bristow, Robert G

AU - Alman, Benjamin

AU - Hawkins, Cynthia E

AU - Malkin, David

AU - Clifford, Steven C

AU - Pfister, Stefan M

AU - Taylor, Michael D

AU - Tabori, Uri

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

U2 - 10.1186/s40478-014-0174-y

DO - 10.1186/s40478-014-0174-y

M3 - SCORING: Journal article

C2 - 25539912

VL - 2

SP - 174

JO - ACTA NEUROPATHOL COM

JF - ACTA NEUROPATHOL COM

SN - 2051-5960

ER -