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Lookup NU author(s): Dr Venetia BigleyORCiD, Dr Rachel Dickinson, Professor Matthew CollinORCiD
This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Society of Hematology, 2017.
For re-use rights please refer to the publisher's terms and conditions.
© 2017, American Society of Hematology. All rights reserved. Heterozygous GATA2 mutation is associated with immunodeficiency, lymphedema, and myelodysplastic syndrome. Disease presentation is variable, often coinciding with loss of circulating dendritic cells, monocytes, B cells, and natural killer (NK) cells. Nonetheless, in a proportion of patients carrying GATA2 mutation, NK cells persist. We found that peripheral blood NK cells in symptomatic patients uniformly lacked expression of the transcription factor promyelocytic leukemia zinc finger (PLZF), as well as expression of intracellular signaling proteins Fc«Rg, spleen tyrosine kinase (SYK), and EWS/FLI1-Activated Transcript 2 (EAT-2) in a variegated manner. Moreover, consistent with an adaptive identity, NK cells from patients with GATA2 mutation displayed altered expression of cytotoxic granule constituents and produced interferon-g upon Fc-receptor engagement but not following combined interleukin-12 (IL-12) and IL-18 stimulation. Canonical, PLZF-expressing NK cells were retained in asymptomatic carriers of GATA2 mutation. Developmentally, GATA-binding protein-2 (GATA-2) was expressed in hematopoietic stem cells, but not in NK-cell progenitors, CD32CD56bright, canonical, or adaptive CD32CD56dim NK cells. Peripheral blood NK cells from individuals with GATA2 mutation proliferated normally in vitro, whereas lineage-negative progenitors displayed impaired NK-cell differentiation. In summary, adaptive NK cells can persist in patients with GATA2 mutation, even after NK-cell progenitors expire. Moreover, our data suggest that adaptive NK cells are more long-lived than canonical, immunoregulatory NK cells.
Author(s): Schlums H, Jung M, Han H, Theorell J, Bigley V, Chiang SCC, Allan DSJ, Davidson-Moncada JK, Dickinson RE, Holmes TD, Hsu AP, Townsley D, Winkler T, Wang W, Aukrust P, Nordøy I, Calvo KR, Holland SM, Collin M, Dunbar CE, Bryceson YT
Publication type: Article
Publication status: Published
Journal: Blood
Year: 2017
Volume: 129
Issue: 14
Pages: 1927-1939
Print publication date: 06/04/2017
Online publication date: 06/04/2017
Acceptance date: 02/02/2017
Date deposited: 26/01/2018
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020
Publisher: American Society of Hematology
URL: https://doi.org/10.1182/blood-2016-08-734236
DOI: 10.1182/blood-2016-08-734236
PubMed id: 28209719
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