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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 provoke...

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Main Authors: Ahmad, Shiekh Tanveer (Author) , Li, Yiran (Author) , Garcia-Lopez, Jesus (Author) , Gudenas, Brian L. (Author) , Hadley, Jennifer (Author) , Paul, Leena (Author) , Wu, Stephanie C. (Author) , Refaat, Alaa (Author) , Kojic, Marija (Author) , Batts, Melissa (Author) , Soliman, Taha (Author) , Pitre, Aaron (Author) , Arnskötter, Frederik (Author) , Zindy, Frederique (Author) , Jones, Alun (Author) , Twarog, Nathaniel R. (Author) , Mayasundari, Anand (Author) , Bianski, Brandon (Author) , Tinkle, Christopher (Author) , Shirinifard, Abbas (Author) , Janke, Laura (Author) , Lu, Meifen (Author) , Lewis, Sara A. (Author) , Onar-Thomas, Arzu (Author) , Pfister, Stefan (Author) , Gajjar, Amar (Author) , Baker, Suzanne J. (Author) , Roussel, Martine F. (Author) , Rankovic, Zoran (Author) , Robinson, Giles W. (Author) , Orr, Brent A. (Author) , Wainwright, Brandon (Author) , Shelat, Anang A. (Author) , Waszak, Sebastian M. (Author) , Kutscher, Lena M. (Author) , Lin, Hong (Author) , Northcott, Paul A. (Author)
Format: Article (Journal)
Language:English
Published: 9 June 2025
In: Cancer cell
Year: 2025, Volume: 43, Issue: 6, Pages: 1141-1158.e11
ISSN:1878-3686
DOI:10.1016/j.ccell.2025.04.014
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.ccell.2025.04.014
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1535610825001734
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Author Notes:Shiekh Tanveer Ahmad, Yiran Li, Jesus Garcia-Lopez, Brian L. Gudenas, Jennifer Hadley, Leena Paul, Stephanie C. Wu, Alaa Refaat, Marija Kojic, Melissa Batts, Taha Soliman, Aaron Pitre, Frederik Arnskötter, Frederique Zindy, Alun Jones, Nathaniel R. Twarog, Anand Mayasundari, Brandon Bianski, Christopher Tinkle, Abbas Shirinifard, Laura Janke, Meifen Lu, Sara A. Lewis, Arzu Onar-Thomas, Stefan M. Pfister, Amar Gajjar, Suzanne J. Baker, Martine F. Roussel, Zoran Rankovic, Giles W. Robinson, Brent A. Orr, Brandon Wainwright, Anang A. Shelat, Sebastian M. Waszak, Lena M. Kutscher, Hong Lin, and Paul A. Northcott
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Summary: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.
Item Description:Online verfügbar: 15. Mai 2025, Artikelversion: 9. Juni 2025
Gesehen am 27.10.2025
Physical Description:Online Resource
ISSN:1878-3686
DOI:10.1016/j.ccell.2025.04.014

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