Journal Article

DKFZ-2025-01851

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Posttranscriptional depletion of ribosome biogenesis factors engenders therapeutic vulnerabilities in NPM1-mutant AML.

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.DKFZ* ; Papachristou, E. K. ; Sawle, A. ; Yankova, E. ; Dudek, M. ; Liu, X. ; Russell, J. ; Rak, J. ; Hilcenko, C. ; D'Santos, C. ; Jeremias, I.DKFZ* ; Sarry, J.-E. ; Tzelepis, K. ; Huntly, B. J. P. ; Warren, A. J. ; Tavana, O. ; Vassiliou, G. S.

2025
American Society of Hematology Washington, DC

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Please use a persistent id in citations: doi:10.1182/blood.2024026113

Abstract: NPM1 is a multifunctional phosphoprotein with key roles in ribosome biogenesis among its many functions. NPM1 gene mutations drive 30% of acute myeloid leukemia (AML) cases. The mutations disrupt a nucleolar localization signal and create a novel nuclear export signal, 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 evaluate the effects of isolated NPM1c mutations on the global proteome of preleukemic hematopoietic stem and progenitor cells (HSPCs) using conditional knockin 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 preleukemic Npm1cA/+ HSPCs display higher sensitivity to RNA polymerase I inhibitors, including actinomycin D (ActD), compared with Npm1+/+ cells. Combination treatment with ActD and venetoclax inhibited the growth and colony-forming ability of preleukemic and leukemic NPM1c+ cells, whereas low-dose ActD treatment was able to resensitize resistant NPM1c+ cells to venetoclax. Furthermore, using data from CRISPR dropout screens, we identified and validated TSR3, a 40S ribosomal maturation factor whose knockout 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.

Keyword(s): Nucleophosmin (MeSH) ; Leukemia, Myeloid, Acute: genetics (MeSH) ; Leukemia, Myeloid, Acute: drug therapy (MeSH) ; Leukemia, Myeloid, Acute: pathology (MeSH) ; Leukemia, Myeloid, Acute: metabolism (MeSH) ; Animals (MeSH) ; Nuclear Proteins: genetics (MeSH) ; Nuclear Proteins: metabolism (MeSH) ; Mice (MeSH) ; Humans (MeSH) ; Ribosomes: metabolism (MeSH) ; Ribosomes: genetics (MeSH) ; Mutation (MeSH) ; Bridged Bicyclo Compounds, Heterocyclic: pharmacology (MeSH) ; Sulfonamides: pharmacology (MeSH) ; Hematopoietic Stem Cells: metabolism (MeSH) ; Hematopoietic Stem Cells: pathology (MeSH) ; Dactinomycin: pharmacology (MeSH) ; Nucleophosmin ; Npm1 protein, mouse ; Nuclear Proteins ; NPM1 protein, human ; venetoclax ; Bridged Bicyclo Compounds, Heterocyclic ; Sulfonamides ; Dactinomycin

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Contributing Institute(s):

1. DKTK Koordinierungsstelle München (MU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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