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@ARTICLE{Hruby:302992,
      author       = {L. Hruby and K. Schaal and A. Delaidelli and D. J.
                      Picard$^*$ and C. Dunham and O. Lewandowska and T. Reiff and
                      M. Larcher and C. Pouponnot and P. H. Sorensen and B.
                      Rotblat and G. Reifenberger$^*$ and M. Remke$^*$ and G.
                      Leprivier},
      title        = {{T}he {EIF}4{EBP}1 gene encoding 4{EBP}1 is
                      transcriptionally upregulated by {MYC} and linked to shorter
                      survival in medulloblastoma.},
      journal      = {Cell death discovery},
      volume       = {11},
      number       = {1},
      issn         = {2058-7716},
      address      = {London},
      publisher    = {Nature Publishing Group},
      reportid     = {DKFZ-2025-01439},
      pages        = {330},
      year         = {2025},
      abstract     = {Medulloblastoma (MB) is the most common malignant brain
                      tumor in childhood and is stratified into four molecular
                      groups ‒ Wingless and Int-1 (WNT), Sonic hedgehog (SHH),
                      Group 3 and Group 4. Group 3 MB patients exhibit the poorest
                      prognosis, with a 5-year overall survival of $<60\%,$
                      followed by Group 4 MB patients. Apart from MYC
                      amplification in a subset of Group 3 MBs, the molecular
                      pathomechanisms driving aggressiveness of these tumors
                      remain incompletely characterized. The gene encoding the
                      mTOR substrate and mRNA translation inhibitor eukaryotic
                      translation initiation factor 4E-binding protein 1
                      (EIF4EBP1) represents a possible MYC target gene whose
                      corresponding protein, 4EBP1, was shown to be more active in
                      Group 3 versus Group 4 MBs. However, the prognostic role of
                      4EBP1 in MB and the mechanisms supporting 4EBP1
                      overexpression in Group 3 MB are still elusive. We analyzed
                      EIF4EBP1 mRNA expression in publicly available data sets and
                      found an upregulation in MB as compared to non-neoblastic
                      brain. EIF4EBP1 mRNA expression levels were higher in Group
                      3 compared to Group 4 MBs. EIF4EBP1 mRNA expression was
                      correlated with MYC expression, most prominently in Group 3
                      MBs. Survival analyses highlighted that high EIF4EBP1 mRNA
                      expression was associated with reduced overall and
                      event-free survival across all MB patients and in Group
                      3/Group 4 MB patients. Immunohistochemical evaluation of
                      4EBP1 protein expression in MB tissues confirmed that high
                      levels of 4EBP1 are associated with poor outcome. Functional
                      analyses revealed that MYC directly regulates EIF4EBP1
                      promoter activity, providing a mechanism for increased
                      EIF4EBP1 mRNA levels in Group 3 MBs. Finally, we observed
                      that 4EBP1 may support colony formation of in vitro cultured
                      MB cells. Our data highlight that transcriptional
                      upregulation of EIF4EBP1 by MYC promotes in vitro
                      tumorigenicity of MB cells and associates with shorter
                      survival of MB patients.},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40670359},
      pmc          = {pmc:PMC12267489},
      doi          = {10.1038/s41420-025-02601-x},
      url          = {https://inrepo02.dkfz.de/record/302992},
}