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  • Mainwaring, OliverUppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab,Fredrik Swartling (author)

ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2023-03-03
  • Springer Nature,2023
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-469075
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-469075URI
  • https://doi.org/10.1038/s41467-023-36847-9DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:153826414URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • De två första författarna delar förstaförfattarskapet.
  • Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC-amplified medulloblastomas often show increased photoreceptor activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN-expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC-expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN-expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Weishaupt, HolgerUppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi(Swepub:uu)holwe849 (author)
  • Zhao, MiaoUppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)miazh358 (author)
  • Rosén, GabrielaUppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi(Swepub:uu)gabca335 (author)
  • Borgenvik, Anna,1987-Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi(Swepub:uu)annbo680 (author)
  • Breinschmid, LauraUppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab (author)
  • Verbaan, Annemieke D.Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab (author)
  • Richardson, StaceyWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK. (author)
  • Thompson, DeanWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK. (author)
  • Clifford, Steven C.Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK. (author)
  • Hill, Rebecca M.Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK. (author)
  • Annusver, KarlKarolinska Institutet (author)
  • Sundström, AndersUppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)andsu781 (author)
  • Holmberg Olausson, KarlUppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)karho832 (author)
  • Kasper, MariaKarolinska Institutet (author)
  • Hutter, SonjaUppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi(Swepub:uu)sonhu330 (author)
  • Swartling, Fredrik J.,1975-Uppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)fredjoha (author)
  • Uppsala universitetNeuroonkologi (creator_code:org_t)

Related titles

  • In:Nature Communications: Springer Nature142041-1723

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