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Ppm1d truncating mutations promote the development of genotoxic stress-induced AML
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SYSNO ASEP 0578776 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Ppm1d truncating mutations promote the development of genotoxic stress-induced AML Author(s) Burocziová, Monika (UMG-J)
Daněk, Petr (UMG-J)
Oravetzová, Anna (UMG-J)
Chalupová, Zuzana (UMG-J)
Alberich-Jorda, Meritxell (UMG-J) RID
Macůrek, Libor (UMG-J) RID, ORCIDNumber of authors 6 Source Title Leukemia. - : Springer - ISSN 0887-6924
Roč. 37, Sep (2023), s. 2209-2220Number of pages 12 s. Language eng - English Country DE - Germany Keywords cell self-renewal ; stem-cell ; phosphatase wip1 ; p53 ; cycle ; hematopoiesis ; tumorigenesis ; quiescence ; maturation ; proteins OECD category Biochemistry and molecular biology R&D Projects GA20-11931S GA ČR - Czech Science Foundation (CSF) LX22NPO5102 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018129 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0016045 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 001065539400001 EID SCOPUS 85170848706 DOI 10.1038/s41375-023-02030-8 Annotation Hematopoietic stem cells (HSCs) ensure blood cell production during the life-time of an organism, and to do so they need to balance self-renewal, proliferation, differentiation, and migration in a steady state as well as in response to stress or injury. Importantly, aberrant proliferation of HSCs leads to hematological malignancies, and thus, tight regulation by various tumor suppressor pathways, including p53, is essential. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and promotes cell survival upon induction of genotoxic stress. Truncating mutations in the last exon of PPM1D lead to the production of a stable, enzymatically active protein and are commonly associated with clonal hematopoiesis. Using a transgenic mouse model, we demonstrate that truncated PPM1D reduces self-renewal of HSCs in basal conditions but promotes the development of aggressive AML after exposure to ionizing radiation. Inhibition of PPM1D suppressed the colony growth of leukemic stem and progenitor cells carrying the truncated PPM1D, and remarkably, it provided protection against irradiation-induced cell growth. Altogether, we demonstrate that truncated PPM1D affects HSC maintenance, disrupts normal hematopoiesis, and that its inhibition could be beneficial in the context of therapy-induced AML. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2024 Electronic address https://www.nature.com/articles/s41375-023-02030-8
Number of the records: 1