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@ARTICLE{Hagemann:276321,
      author       = {S. Hagemann and D. Misiak and J. L. Bell and T. Fuchs and
                      M. I. Lederer and N. Bley and M. Hämmerle and E. Ghazy and
                      W. Sippl and J. Schulte$^*$ and S. Hüttelmaier},
      title        = {{IGF}2{BP}1 induces neuroblastoma via a druggable
                      feedforward loop with {MYCN} promoting 17q oncogene
                      expression.},
      journal      = {Molecular cancer},
      volume       = {22},
      number       = {1},
      issn         = {1476-4598},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2023-01051},
      pages        = {88},
      year         = {2023},
      abstract     = {Neuroblastoma is the most common solid tumor in infants
                      accounting for approximately $15\%$ of all cancer-related
                      deaths. Over $50\%$ of high-risk neuroblastoma relapse,
                      emphasizing the need of novel drug targets and therapeutic
                      strategies. In neuroblastoma, chromosomal gains at
                      chromosome 17q, including IGF2BP1, and MYCN amplification at
                      chromosome 2p are associated with adverse outcome. Recent,
                      pre-clinical evidence indicates the feasibility of direct
                      and indirect targeting of IGF2BP1 and MYCN in cancer
                      treatment.Candidate oncogenes on 17q were identified by
                      profiling the transcriptomic/genomic landscape of 100 human
                      neuroblastoma samples and public gene essentiality data.
                      Molecular mechanisms and gene expression profiles underlying
                      the oncogenic and therapeutic target potential of the 17q
                      oncogene IGF2BP1 and its cross-talk with MYCN were
                      characterized and validated in human neuroblastoma cells,
                      xenografts and PDX as well as novel IGF2BP1/MYCN transgene
                      mouse models.We reveal a novel, druggable feedforward loop
                      of IGF2BP1 (17q) and MYCN (2p) in high-risk neuroblastoma.
                      This promotes 2p/17q chromosomal gains and unleashes an
                      oncogene storm resulting in fostered expression of 17q
                      oncogenes like BIRC5 (survivin). Conditional,
                      sympatho-adrenal transgene expression of IGF2BP1 induces
                      neuroblastoma at a $100\%$ incidence. IGF2BP1-driven
                      malignancies are reminiscent to human high-risk
                      neuroblastoma, including 2p/17q-syntenic chromosomal gains
                      and upregulation of Mycn, Birc5, as well as key
                      neuroblastoma circuit factors like Phox2b. Co-expression of
                      IGF2BP1/MYCN reduces disease latency and survival
                      probability by fostering oncogene expression. Combined
                      inhibition of IGF2BP1 by BTYNB, MYCN by BRD inhibitors or
                      BIRC5 by YM-155 is beneficial in vitro and, for BTYNB,
                      also.We reveal a novel, druggable neuroblastoma oncogene
                      circuit settling on strong,
                      transcriptional/post-transcriptional synergy of MYCN and
                      IGF2BP1. MYCN/IGF2BP1 feedforward regulation promotes an
                      oncogene storm harboring high therapeutic potential for
                      combined, targeted inhibition of IGF2BP1, MYCN expression
                      and MYCN/IGF2BP1-effectors like BIRC5.},
      keywords     = {17q gain (Other) / BIRC5 (survivin) (Other) / BTYNB (Other)
                      / IGF2BP1 (Other) / MYCN (Other) / Mivebresib (Other) /
                      Neuroblastoma (Other) / PDX (Other) / RNA-binding protein
                      (RBP) (Other) / Transgenic mouse model (Other) / YM-155
                      (Other)},
      cin          = {BE01},
      ddc          = {570},
      cid          = {I:(DE-He78)BE01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37246217},
      doi          = {10.1186/s12943-023-01792-0},
      url          = {https://inrepo02.dkfz.de/record/276321},
}