NPM1 ablation induces HSC aging and inflammation to develop myelodysplastic syndrome exacerbated by p53 loss

Claudia Morganti, Kyoko Ito, Chie Yanase, Amit Verma, Julie Teruya-Feldstein, Keisuke Ito

Research output: Contribution to journalArticlepeer-review

Abstract

Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with morphologic dysplasia and a propensity to transform into overt acute myeloid leukemia (AML). Our analysis of two cohorts of 20 MDS and 49 AML with multi-lineage dysplasia patients shows a reduction in Nucleophosmin 1 (NPM1) expression in 70% and 90% of cases, respectively. A mouse model of Npm1 conditional knockout (cKO) in hematopoietic cells reveals that Npm1 loss causes premature aging of hematopoietic stem cells (HSCs). Mitochondrial activation in Npm1-deficient HSCs leads to aberrant activation of the NLRP3 inflammasome, which correlates with a developing MDS-like phenotype. Npm1 cKO mice exhibit shortened survival times, and expansion of both the intra- and extra-medullary myeloid populations, while evoking a p53-dependent response. After transfer into a p53 mutant background, the resulting Npm1/p53 double KO mice develop fatal leukemia within 6 months. Our findings identify NPM1 as a regulator of HSC aging and inflammation and highlight the role of p53 in MDS progression to leukemia.

Original languageEnglish (US)
Article numbere54262
JournalEMBO Reports
Volume23
Issue number5
DOIs
StatePublished - May 4 2022

Keywords

  • HSC aging
  • MDS
  • Nlrp3
  • Npm1
  • Tp53

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint

Dive into the research topics of 'NPM1 ablation induces HSC aging and inflammation to develop myelodysplastic syndrome exacerbated by p53 loss'. Together they form a unique fingerprint.

Cite this