Journal Article DKFZ-2025-01007

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

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2025
Cell Press Cambridge, Mass.

Cancer cell 43(6), 1141-1158.e11 () [10.1016/j.ccell.2025.04.014]
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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.

Keyword(s): ELP1 ; Elongator complex ; Sonic hedgehog signaling ; cerebellar development ; childhood cancer predisposition ; genetically engineered mouse models ; granule neuron progenitors ; in vivo preclinical studies ; medulloblastoma ; multi-omics

Classification:

Note: 2025 Jun 9;43(6):1141-1158.e11

Contributing Institute(s):
  1. Entwicklungsbiolog. Ursprünge pädiatrischer Krebserkrankungen (B430)
  2. B062 Pädiatrische Neuroonkologie (B062)
  3. DKTK HD zentral (HD01)
Research Program(s):
  1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025
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Medline ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 50 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection
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 Record created 2025-05-19, last modified 2025-06-11



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