PXD045010

PXD045010 is an original dataset announced via ProteomeXchange.

Title	Reduced PRC2 function causes asparaginase resistance in T-ALL by decreasing WNT pathway activity
Description	Loss-of-function mutations and deletions in the core components of the epigenetic polycomb repressive complex 2 (PRC2) are associated with poor initial treatment response in T-cell acute lymphoblastic leukemia (T-ALL), but the mechanisms that underpin resistance to individual therapies are unknown. We leveraged an isogenic T-ALL cellular model and primary patient data to investigate how PRC2 alterations affect signaling pathway activity in leukemia cells, and whether these changes may influence therapy response. The integration of transcriptomic, proteomic, and phosphoproteomic results revealed markedly reduced activity of the WNT-dependent stabilization of proteins (WNT/STOP) pathway in leukemia cells lacking core PRC2 factor EZH2. Importantly, these results closely matched transcriptional readouts from the samples of patients with T-ALL with PRC2 mutations and deletions. We discovered that PRC2 loss significantly reduced sensitivity to key T-ALL treatment asparaginase, and that this was mechanistically linked to increased cellular ubiquitination levels due to WNT/STOP suppression, which bolstered the asparagine reserves of leukemia cells. These results also strongly correlated with transcriptional profiles of asparaginase resistance in an independent cohort of patients with T-ALL. We further found that asparaginase resistance in PRC2-depleted leukemic blasts could be mitigated by pharmaceutical proteasome inhibition, thereby providing a potential avenue to tackle induction treatment failure in these cases.
HostingRepository	PRIDE
AnnounceDate	2025-12-23
AnnouncementXML	Submission_2025-12-23_14:20:27.020.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kieran Wynne
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-31 12:15:52	ID requested
⏵ 1	2025-12-23 14:20:27	announced

Dataset with its publication pending

submitter keyword: None

Prof Jonathon
contact affiliation	Full Professor of Paediatric Molecular Haemato-Oncology School of Medicine,University College Dublin, School of Medicine, Systems Biology Ireland Temple Street Dublin 1
contact email	jonathan.bond@ucd.ie
lab head
Kieran Wynne
contact affiliation	University College Dublin
contact email	kieran.wynne1@ucd.ie
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD045010
     1. Label: PRIDE project
     2. Name: Reduced PRC2 function causes asparaginase resistance in T-ALL by decreasing WNT pathway activity