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@ARTICLE{Ahmad:301369,
      author       = {S. T. Ahmad and Y. Li and J. Garcia-Lopez and B. L. Gudenas
                      and J. Hadley and L. Paul and S. C. Wu and A. Refaat and M.
                      Kojic and M. Batts and T. Soliman and A. Pitre and F.
                      Arnskötter$^*$ and F. Zindy and A. Jones and N. R. Twarog
                      and A. Mayasundari and B. Bianski and C. Tinkle and A.
                      Shirinifard and L. Janke and M. Lu and S. A. Lewis and A.
                      Onar-Thomas and S. M. Pfister$^*$ and A. Gajjar and S. J.
                      Baker and M. F. Roussel and Z. Rankovic and G. W. Robinson
                      and B. A. Orr and B. Wainwright and A. A. Shelat and S. M.
                      Waszak and L. M. Kutscher$^*$ and H. Lin and P. A.
                      Northcott},
      title        = {{G}enetic modeling of {ELP}1-associated {S}onic hedgehog
                      medulloblastoma identifies {MDM}2 as a selective therapeutic
                      target.},
      journal      = {Cancer cell},
      volume       = {43},
      number       = {6},
      issn         = {1535-6108},
      address      = {Cambridge, Mass.},
      publisher    = {Cell Press},
      reportid     = {DKFZ-2025-01007},
      pages        = {1141-1158.e11},
      year         = {2025},
      note         = {2025 Jun 9;43(6):1141-1158.e11},
      abstract     = {Germline loss-of-function (LOF) variants in Elongator
                      acetyltransferase complex subunit 1 (ELP1) are the most
                      prevalent predisposing genetic events in childhood
                      medulloblastoma (MB), accounting for $∼30\%$ of the Sonic
                      hedgehog (SHH) 3 subtype. The mechanism(s) by which germline
                      ELP1 deficiency provokes SHH-MB pathogenesis remain unknown.
                      Genetically engineered mice mimicking heterozygous Elp1 LOF
                      (Elp1HET) seen in affected germline carriers exhibit
                      hallmark features of premalignancy in cerebellar granule
                      neuron progenitors (GNPs), including increased DNA
                      replication stress, genomic instability, accelerated cell
                      cycle, and stalled differentiation. Orthotopic
                      transplantation of Elp1HET GNPs harboring somatic Ptch1
                      inactivation yields SHH-MB-like tumors with compromised p53
                      signaling, providing a plausible explanation for the
                      exclusivity of ELP1-associated MBs in the SHH-3 subtype.
                      Preclinical treatment of ELP1-mutant patient-derived
                      xenografts with an FDA-approved MDM2 inhibitor reactivates
                      p53-dependent apoptosis and extends survival. Our findings
                      functionally substantiate the role of ELP1 deficiency in
                      SHH-MB predisposition and nominate therapeutics targeting
                      MDM2 as a rational treatment option.},
      keywords     = {ELP1 (Other) / Elongator complex (Other) / Sonic hedgehog
                      signaling (Other) / cerebellar development (Other) /
                      childhood cancer predisposition (Other) / genetically
                      engineered mouse models (Other) / granule neuron progenitors
                      (Other) / in vivo preclinical studies (Other) /
                      medulloblastoma (Other) / multi-omics (Other)},
      cin          = {B430 / B062 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B430-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40378836},
      doi          = {10.1016/j.ccell.2025.04.014},
      url          = {https://inrepo02.dkfz.de/record/301369},
}