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@ARTICLE{Treisman:147736,
      author       = {D. M. Treisman and Y. Li and B. R. Pierce and C. Li and A.
                      P. Chervenak and G. J. Tomasek and G. Lozano and X. Zheng
                      and M. Kool$^*$ and Y. Zhu},
      title        = {{S}ox2+ cells in {S}onic {H}edgehog-subtype medulloblastoma
                      resist p53-mediated cell-cycle arrest response and drive
                      therapy-induced recurrence.},
      journal      = {Neuro-oncology advances},
      volume       = {1},
      number       = {1},
      issn         = {2632-2498},
      address      = {Oxford},
      publisher    = {Oxford University Press},
      reportid     = {DKFZ-2019-02713},
      pages        = {vdz027},
      year         = {2019},
      note         = {Neuro-Oncology Advances () = 2632-2498 (import from
                      CrossRef, PubMed, )E-ISSN(s): 2632-2498},
      abstract     = {High-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.},
      cin          = {B062 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)L101-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31763624},
      pmc          = {pmc:PMC6860004},
      doi          = {10.1093/noajnl/vdz027},
      url          = {https://inrepo02.dkfz.de/record/147736},
}