@article{55cb4bde463d45f8ba9cc5683b7b3803,
title = "NPM1 ablation induces HSC aging and inflammation to develop myelodysplastic syndrome exacerbated by p53 loss",
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.",
keywords = "HSC aging, MDS, Nlrp3, Npm1, Tp53",
author = "Claudia Morganti and Kyoko Ito and Chie Yanase and Amit Verma and Julie Teruya-Feldstein and Keisuke Ito",
note = "Funding Information: We are grateful to members of the Ito lab and the Einstein Stem Cell Institute for their comments on hematology and stem cell biology, and especially thank H. Sato for her technical support, K. Gritsman for her critical reading of our manuscript, P.P. Pandolfi for the Npm1F/F mouse strain, as well as the Einstein Flow Cytometry and Analytical Imaging core facilities (funded by National Cancer Institute grant P30 CA013330) for help carrying out the experiments. A. V. and Ke. I. are supported by grants from the National Institutes of Health (R01HL139487 and R01HL150832 to A.V., and R01HL148852, R01DK098263, R01DK115577, and R01HL069438 to K.I., respectively) and New York State Department of Health as Core Director of Einstein Single-Cell Genomics/Epigenomics (C029154). Ke.I. is a Research Scholar of the Leukemia & Lymphoma Society (#1360-19). C.M. is supported by The Einstein Training Program in Stem Cell Research, which is acknowledged from the Empire State Stem Cell Fund through New York State Department of Health Contract (C34874GG). Funding Information: We are grateful to members of the Ito lab and the Einstein Stem Cell Institute for their comments on hematology and stem cell biology, and especially thank H. Sato for her technical support, K. Gritsman for her critical reading of our manuscript, P.P. Pandolfi for the mouse strain, as well as the Einstein Flow Cytometry and Analytical Imaging core facilities (funded by National Cancer Institute grant P30 CA013330) for help carrying out the experiments. A. V. and Ke. I. are supported by grants from the National Institutes of Health (R01HL139487 and R01HL150832 to A.V., and R01HL148852, R01DK098263, R01DK115577, and R01HL069438 to K.I., respectively) and New York State Department of Health as Core Director of Einstein Single‐Cell Genomics/Epigenomics (C029154). Ke.I. is a Research Scholar of the Leukemia & Lymphoma Society (#1360‐19). C.M. is supported by The Einstein Training Program in Stem Cell Research, which is acknowledged from the Empire State Stem Cell Fund through New York State Department of Health Contract (C34874GG). Npm1 F/F Publisher Copyright: {\textcopyright} 2022 The Authors.",
year = "2022",
month = may,
day = "4",
doi = "10.15252/embr.202154262",
language = "English (US)",
volume = "23",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "5",
}