Genetic modeling of ELP1-associated Sonic hedgehog medulloblastoma identifies MDM2 as a selective therapeutic target

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 (Elp1<sub>HET</sub>) 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 Elp1<sub>HET</sub> 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.

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Publication Details

Journal
Cancer Cell
Published
2025-05-15
DOI
https://doi.org/10.1016/j.ccell.2025.04.014
Citations
1
Primary Topic
Hedgehog Signaling Pathway Studies
Type
article
Field-Weighted Citation Impact
0.81

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article

Genetic modeling of ELP1-associated Sonic hedgehog medulloblastoma identifies MDM2 as a selective therapeutic target

Lena M. Kutscher, Brandon J. Wainwright, Jennifer L. Hadley, Martine F. Roussel et al.
1 citations
Cancer Cell
Hedgehog Signaling Pathway Studies
0.81
article

Genetic modeling of ELP1-associated Sonic hedgehog medulloblastoma identifies MDM2 as a selective therapeutic target

Lena M. Kutscher, Brandon J. Wainwright, Jennifer L. Hadley, Martine F. Roussel, Zoran Ranković, Taha Soliman, Jesús García-López, Alaa Refaat, Brent A. Orr, Shiekh Tanveer Ahmad, Abbas Shirinifard, Stuart N. Baker, Aaron Pitre, Amar Gajjar, Stefan M. Pfister, Leena Paul, Brandon Bianski, Paul A. Northcott, Sebastian M. Waszak, Melissa Batts, Christopher L. Tinkle, Giles W Robinson, Brian Gudenas, Frédérique Zindy, Marija Kojic, Nathaniel Twarog, Alun Jones, Meifen Lu, Anand Mayasundari, Arzu Onar‐Thomas, Hong Lin, Stephanie Wu, Sara A. Lewis, Anang A. Shelat, Laura J. Janke, Yiran Li, Frederik Arnskötter
article en
1 citations

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 (Elp1<sub>HET</sub>) 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 Elp1<sub>HET</sub> 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.

Cancer CellVol. 43(6)
St. Jude Children's Research Hospital (US), The University of Queensland (AU), German Cancer Research Center (DE), Heidelberg University (DE), University Hospital Heidelberg (DE), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), École Polytechnique Fédérale de Lausanne (CH)
Deutsche Forschungsgemeinschaft, National Cancer Institute
Zero hunger
Openalex Percentile: Top 28%
Hedgehog Signaling Pathway Studies
0.81
DOIOpen Access PDFOpenAlex
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