Gata2 haploinsufficiency promotes proliferation and functional decline of hematopoietic stem cells with myeloid bias during aging.

Autor:	Abdelfattah A; European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom.; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, Jordan., Hughes-Davies A; European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom., Clayfield L; European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom., Menendez-Gonzalez JB; European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom.; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA., Almotiri A; European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom.; College of Applied Medical Sciences-Dawadmi, Shaqra University, Dawadmi, Saudi Arabia; and., Alotaibi B; European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom., Tonks A; Department of Hematology, Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom., Rodrigues NP; European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2021 Oct 26; Vol. 5 (20), pp. 4285-4290.
DOI:	10.1182/bloodadvances.2021004726
Abstrakt:	During aging, hematopoietic stem cell (HSC) function wanes with important biological and clinical implications for benign and malignant hematology, and other comorbidities, such as cardiovascular disease. However, the molecular mechanisms regulating HSC aging remain incompletely defined. GATA2 haploinsufficiency driven clinical syndromes initially result in primary immunodeficiencies and routinely evolve into hematologic malignancies on acquisition of further epigenetic mutations in both young and older patients. Using a conditional mouse model of Gata2 haploinsufficiency, we discover that during aging Gata2 promotes HSC proliferation, monocytosis, and loss of the common lymphoid progenitor. Aging of Gata2 haploinsufficient mice also offsets enhanced HSC apoptosis and decreased granulocyte-macrophage progenitor number normally observed in young Gata2 haploinsufficient mice. Transplantation of elderly Gata2 haploinsufficient HSCs impairs HSC function with evidence of myeloid bias. Our data demonstrate that Gata2 regulates HSC aging and suggest the mechanisms by which Gata2 mediated HSC aging has an impact on the evolution of malignancies in GATA2 haploinsufficiency syndromes. (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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