MDB-23. ELP1 GERMLINE DEFICIENCY SENSITIZES THE GRANULE NEURON LINEAGE TO SHH MEDULLOBLASTOMA AND EXPOSES NOVEL THERAPEUTIC VULNERABILITIES

Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB). ELP1 germline carriers develop SHH-MBs that exhibit coincident somatic PTCH1 mutations and universal loss-of-heterozygosity of the remaining ELP1 allele through chromosome 9q deletion. The molecular, biochemical, and cellular mechanisms by which germline ELP1/Elongator deficiency contribute to SHH-MB tumorigenesis remain largely unknown. Herein, we report that mice engineered to mimic germline Elp1 LOF (i.e., Elp1(HET)) seen in SHH-MB patients exhibit hallmark features of premalignancy events in cycling cerebellar granule neuron progenitors (GNPs), the lineage-of-origin for SHH-MB. Compared to wild-type counterparts, Elp1(HET) GNPs exhibit increased replication stress-associated DNA damage, homologous recombination-associated genomic instability, accelerated cell cycle kinetics, reduced p53-dependent apoptosis in response to genotoxic stress, and slowed differentiation. Orthotopic transplantation of Elp1(HET) GNPs harboring somatic Ptch1 inactivation into the cerebella of immunocompromised mice promotes onset of SHH-MB tumors with incomplete penetrance that exhibit reduced p53 transcriptional activity through a currently unknown mechanism(s). Concomitant Elp1 and Ptch1 gene targeting in p53-null GNPs reproduces highly penetrant cerebellar tumors recapitulating the molecular and phenotypic features of ELP1-associated SHH-MB. Finally, reactivation of the p53 pathway through preclinical treatment with an MDM2 inhibitor promotes cell death and prolongs the survival of patient-derived xenograft tumor (PDX) models harboring deleterious ELP1 mutations. Together, our findings reveal that germline Elp1 LOF heightens genomic instability and malignant transformation in cycling GNPs, providing a mechanistic model for the subgroup-restricted pattern of predisposition associated with pathogenic ELP1 germline carriers. These results provide essential mechanistic insight into the molecular and cellular basis of SHH-MB predisposition driven by ELP1 LOF and nominate therapies that overcome p53 pathway inhibition as a rational treatment option for affected children.