Proteomics

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Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma


ABSTRACT: Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ~30% of the Sonic Hedgehog (SHH) 3 subtype. The underlying mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous germline Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of cancer predisposition 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 an explanation for the exclusivity of ELP1-associated MBs in SHH-3 subtype. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved HDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics that overcome p53 inhibition as a rational treatment option.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cerebellum

SUBMITTER: Zuo-Fei Yuan  

LAB HEAD: Paul Northcott

PROVIDER: PXD050488 | Pride | 2025-04-11

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
Northcgrp_071321_tTMT_1.1.pepXML Pepxml
Northcgrp_071321_tTMT_1.raw Raw
Northcgrp_071321_tTMT_10.1.pepXML Pepxml
Northcgrp_071321_tTMT_10.raw Raw
Northcgrp_071321_tTMT_11.1.pepXML Pepxml
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