MDB-13. GERMLINEELP1 DEFICIENCY SENSITIZES CEREBELLAR GRANULE NEURON PROGENITORS TO SHH MEDULLOBLASTOMA

BACKGROUND Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events observed in medulloblastoma (MB), accounting for 30% of the Sonic Hedgehog 3 subtype (SHH-3). Molecularly, ELP1-associated SHH-MBs acquire somatic PTCH1 mutations in >80% of cases, and universal loss-of-heterozygosity of the wild-type ELP1 and PTCH1 alleles through loss of chromosome-arm 9q, resulting in their biallelic inactivation. Notably, germline ELP1 LOF occurs mutually exclusive with somatic/germline TP53 mutations in the SHH-3 subtype, suggesting that genetic perturbation of either ELP1 or TP53 may promote similar tumorigenic consequences in cerebellar granule neuron progenitors (GNPs), the accepted cellular origin of SHH-MB. Despite these findings, the molecular, biochemical, and cellular mechanism(s) by which ELP1-deficiency provokes malignant pathogenesis remain unknown. In this study, we sought to close this knowledge gap and functionally determine why children harboring pathogenic ELP1 germline variants are at an increased risk of developing SHH-MB. METHODS Mice were genetically engineered to mimic heterozygous Elp1 LOF (Elp1HET). We studied the effect of Elp1 LOF in GNPs using a combination of molecular profiling, immunophenotyping, and cellular assays. RESULTS GNPs from Elp1HET mice exhibited a spectrum of molecular and biochemical hallmarks of malignant transformation including increased DNA replication stress, DNA damage, accelerated cell cycle progression, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs engineered to harbor somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the specificity of ELP1-associated tumors in SHH-3, and their exclusivity with TP53-mutant tumors. Treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. CONCLUSIONS Collectively, our findings functionally substantiate the role of ELP1 deficiency in predisposition to SHH-3 MB and nominate therapeutic strategies to overcome p53 inhibition as a rational treatment option.