PXD053249

PXD053249 is an original dataset announced via ProteomeXchange.

Title	Ribosome biogenesis factors are post-transcriptionally depleted in NPM1-mutant acute myeloid leukemia and can be targeted therapeutically
Description	Mutations in the NPM1 gene are found in more than 30% of acute myeloid leukemia (AML) cases. The mutations disrupt a nucleolar localization signal (NoLS) and create a novel nuclear export signal (NES), leading to cytoplasmic displacement of the protein (NPM1c). NPM1c mutations prime hematopoietic progenitors to leukemic transformation, but their precise molecular consequences remain elusive. Here, we first examine the effects of isolated NPM1c mutations on the global proteome of pre-leukemic hematopoietic stem and progenitor cells (HSPCs) using conditional knock-in Npm1cA/+ mice. We discovered that many proteins involved in ribosome biogenesis are significantly depleted in these HSPCs, but also importantly in human NPM1-mutant AMLs. In line with this, we found that pre-leukemic Npm1cA/+ HSPCs display higher sensitivity to RNA pol I inhibitors, including Actinomycin D (ActD), compared to Npm1+/+ cells. Combination treatment with ActD and Venetoclax inhibited the growth and colony forming ability of pre-leukemic and leukemic NPM1c+ cells and low-dose ActD treatment was able to re-sensitize resistant NPM1c+ cells to Venetoclax. Furthermore, using data from CRISPR drop-out screens, we identified and validated TSR3, a 40S ribosomal maturation factor whose knock-out preferentially inhibited the proliferation of NPM1c+ AML cells by activating a p53-dependent apoptotic response. Similarly to low-dose ActD treatment, TSR3 depletion could partially restore sensitivity to Venetoclax in therapy-resistant NPM1c+ AML models.
HostingRepository	PRIDE
AnnounceDate	2025-05-27
AnnouncementXML	Submission_2025-05-27_07:08:16.416.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Evangelia Papachristou
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-20 06:11:01	ID requested
⏵ 1	2025-05-27 07:08:16	announced

Dataset with its publication pending

submitter keyword: NPM1, proteomics, TMT,ribososme biogenesis

George S. Vassiliou
contact affiliation	1. Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom. 2. Department of Haematology, University of Cambridge, Cambridge, United Kingdom. 3.6. Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom.
contact email	gsv20@cam.ac.uk
lab head
Evangelia Papachristou
contact affiliation	Senior Scientific Assistant
contact email	Eva.Papachristou@cruk.cam.ac.uk
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/2025/05/PXD053249

PRIDE project URI

• PRIDE
  1. PXD053249
     1. Label: PRIDE project
     2. Name: Ribosome biogenesis factors are post-transcriptionally depleted in NPM1-mutant acute myeloid leukemia and can be targeted therapeutically