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 (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 yielded 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 reactivated p53-dependent apoptosis and extended survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics targeting MDM2 as a rational treatment option. Transcriptome profiling by scRNA-seq in the developing cerebellum from wild-type and Elp1+/- mice at P7. The study included six replicates in each group (five single mouse samples and one pooled sample per group). snRNA-seq data were generated for mouse tumors from orthotopic transplantation models.