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Damaskou, A.* ; Wilson, R.* ; Gozdecka, M.* ; Giotopoulos, G.* ; Asby, R.* ; Eleftheriou, M.* ; Gu, M.* ; Récher, C.* ; Mansat-De Mas, V.* ; Vergez, F.* ; Sahal, A.* ; Vick, B. ; Papachristou, E.K.* ; Sawle, A.* ; Yankova, E.* ; Dudek, M.* ; Liu, X.* ; Russell, J.* ; Rak, J.* ; Hilcenko, C.* ; D'Santos, C.S.* ; Jeremias, I. ; Sarry, J.E.* ; Tzelepis, K.* ; Huntly, B.J.* ; Warren, A.J.* ; Tavana, O.* ; Vassiliou, G.S.*

Posttranscriptional depletion of ribosome biogenesis factors engenders therapeutic vulnerabilities in NPM1-mutant AML.

Blood 146, 1239-1252 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
NPM1 is a multifunctional phosphoprotein with key roles in ribosome biogenesis amongst its many functions. NPM1 gene mutations drive 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 discover that many proteins involved in ribosome biogenesis are significantly depleted in these murine 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 polymerase 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, whilst low-dose ActD treatment was able to re-sensitize resistant NPM1c+ cells to Venetoclax. Furthermore, using data from CRISPR dropout 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. Our findings propose that targeted disruption of ribosome biogenesis should be explored as a therapeutic strategy against NPM1-mutant AML.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Myeloid-leukemia; Molecular-basis; Nucleophosmin; Proteins; Inhibition; Drugs; Yeast; L5
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 146, Issue: 10, Pages: 1239-1252 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Stem Cell and Neuroscience
PSP Element(s) G-506600-001
Grants European Regional Development Fund through the Interreg V-A Spain-France-Andorra
UKRI Medical Research Council
Wellcome Trust
Rising Tide Foundation for Clinical Cancer Research, Kay Kendall Leukaemia Fund, Blood Cancer UK
European Research Council
Cancer Research UK Senior Cancer Fellowship
Leukaemia UK
Leukaemia UK John Goldman Fellowship
Laboratoire d'Excellence Toulouse Cancer (TOUCAN)
Programme Investissement d'Avenir Projets de Recherche et Dveloppement Structurants Pour la Comptitivit (Initiative de Mod e`les Innovants)
Addenbrookes Charitable Trust
Isaac Newton Trust
Rosetrees Trust
Blood Cancer UK
European Cooperation in Science and Technology
UK Medical Research Council
Cancer Research UK
DOI 10.1182/blood.2024026113
WOS ID 001568651900015
Scopus ID 105012092614
PubMed ID 40561247
Erfassungsdatum 2025-06-26
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