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000147736 1001_ $$aTreisman, Daniel M$$b0
000147736 245__ $$aSox2+ cells in Sonic Hedgehog-subtype medulloblastoma resist p53-mediated cell-cycle arrest response and drive therapy-induced recurrence.
000147736 260__ $$aOxford$$bOxford University Press$$c2019
000147736 264_1 $$2Crossref$$3online$$bOxford University Press (OUP)$$c2019-09-23
000147736 264_1 $$2Crossref$$3print$$bOxford University Press (OUP)$$c2019-05-01
000147736 264_1 $$2Crossref$$3print$$bOxford University Press (OUP)$$c2019-05-01
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000147736 500__ $$a Neuro-Oncology Advances () = 2632-2498 (import from CrossRef, PubMed, )E-ISSN(s): 2632-2498
000147736 520__ $$aHigh-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.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.Upon radiation treatment, p53WT-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 p53R172P, an apoptosis-defective allele with cell-cycle arrest activity, via inducing robust neuronal differentiation. Rare quiescent Sox2+ cells survived radiation-enhanced p53R172P 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.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.
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000147736 7001_ $$aLi, Yinghua$$b1
000147736 7001_ $$aPierce, Brianna R$$b2
000147736 7001_ $$aLi, Chaoyang$$b3
000147736 7001_ $$aChervenak, Andrew P$$b4
000147736 7001_ $$aTomasek, Gerald J$$b5
000147736 7001_ $$aLozano, Guillermina$$b6
000147736 7001_ $$aZheng, Xiaoyan$$b7
000147736 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b8$$udkfz
000147736 7001_ $$aZhu, Yuan$$b9
000147736 77318 $$2Crossref$$3journal-article$$a10.1093/noajnl/vdz027$$bOxford University Press (OUP)$$d2019-05-01$$n1$$tNeuro-Oncology Advances$$v1$$x2632-2498$$y2019
000147736 773__ $$0PERI:(DE-600)3009682-0$$a10.1093/noajnl/vdz027$$gVol. 1, no. 1, p. vdz027$$n1$$pvdz027$$tNeuro-oncology advances$$v1$$x2632-2498$$y2019
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