PXD050487

PXD050487 is an original dataset announced via ProteomeXchange.

Title	Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-04-11
AnnouncementXML	Submission_2025-04-11_07:32:53.405.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Zuo-Fei Yuan
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-08 09:30:09	ID requested
⏵ 1	2025-04-11 07:32:53	announced

Dataset with its publication pending

submitter keyword: medulloblastoma, SHH-3 MB, p53 signaling, tumor predisposition, GNP,Elp1

Paul Northcott
contact affiliation	Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
contact email	paul.northcott@stjude.org
lab head
Zuo-Fei Yuan
contact affiliation	St. Jude Children's Research Hospital
contact email	zuo-fei.yuan@stjude.org
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/04/PXD050487

PRIDE project URI

• PRIDE
  1. PXD050487
     1. Label: PRIDE project
     2. Name: Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma