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@ARTICLE{Funk:305417,
      author       = {C. Funk$^*$ and A. Ehlers$^*$ and M. F. Orth and K.
                      Aljakouch$^*$ and J. Li$^*$ and T. L. Hoelting$^*$ and R.
                      Will$^*$ and F. H. Geyer$^*$ and A. K. Ceranski$^*$ and F.
                      Willis and E. Vinca$^*$ and S. Ohmura$^*$ and R. Imle$^*$
                      and J. Siebenlist$^*$ and A. Yershova$^*$ and M. M. Knott
                      and F. Zahnow$^*$ and A. Sastre and J. Alonso and F.
                      Sahm$^*$ and H. Peterziel and A. Loboda and M. Schneider and
                      A. Banito$^*$ and G. Leprivier and W. Hartmann and U.
                      Dirksen and O. Witt$^*$ and I. Oehme$^*$ and S. M.
                      Pfister$^*$ and L. Romero-Pérez$^*$ and J. Krijgsveld$^*$
                      and F. Cidre-Aranaz$^*$ and T. Grünewald$^*$ and J.
                      Musa$^*$},
      title        = {{H}igh 4{E}-{BP}-1 expression associates with chromosome 8
                      gain and {CDK}4/6 sensitivity in {E}wing {S}arcoma.},
      journal      = {The journal of clinical investigation},
      volume       = {nn},
      issn         = {0021-9738},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DKFZ-2025-02146},
      pages        = {nn},
      year         = {2025},
      note         = {#EA:B410#LA:B410# / epub},
      abstract     = {Chromosome 8 (chr8) gains are common in cancer, but their
                      contribution to tumor heterogeneity is largely unexplored.
                      Ewing sarcoma (EwS) is defined by FET::ETS fusions with few
                      other recurrent mutations to explain clinical diversity. In
                      EwS, chr8 gains are the second most frequent alteration,
                      making it an ideal model to study their relevance in an
                      otherwise silent genomic context. We report that chr8
                      gain-driven expression patterns correlate with poor overall
                      survival of EwS patients. This effect is mainly mediated by
                      increased expression of the translation initiation factor
                      binding protein 4E-BP1, encoded by EIF4EBP1 on chr8. Among
                      all chr8-encoded genes, EIF4EBP1 expression showed the
                      strongest association with poor survival and correlated with
                      chr8 gains in EwS tumors. Similar findings emerged across
                      multiple TCGA cancer entities. Multi-omics profiling
                      revealed that 4E-BP1 orchestrates a pro-proliferative
                      proteomic network. Silencing 4E-BP1 reduced proliferation,
                      clonogenicity, spheroidal growth in vitro, and tumor growth
                      in vivo. Drug screens demonstrated that high 4E-BP1
                      expression sensitizes EwS to pharmacological
                      CDK4/6-inhibition. Chr8 gains and elevated 4E-BP1 emerge as
                      prognostic biomarkers in EwS, with poor outcomes driven by
                      4E-BP1-mediated pro-proliferative networks that sensitize
                      tumors to CDK4/6 inhibitors. Testing for chr8 gains may
                      enhance risk stratification and therapy in EwS and other
                      cancers.},
      keywords     = {Cancer (Other) / Genetic variation (Other) / Genetics
                      (Other) / Mouse models (Other) / Oncology (Other)},
      cin          = {B410 / B230 / W111 / B380 / B300 / B310 / B062},
      ddc          = {610},
      cid          = {I:(DE-He78)B410-20160331 / I:(DE-He78)B230-20160331 /
                      I:(DE-He78)W111-20160331 / I:(DE-He78)B380-20160331 /
                      I:(DE-He78)B300-20160331 / I:(DE-He78)B310-20160331 /
                      I:(DE-He78)B062-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41100815},
      doi          = {10.1172/JCI187627},
      url          = {https://inrepo02.dkfz.de/record/305417},
}