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The evolution of cellular deficiency in GATA2 mutation

Lookup NU author(s): Dr Rachel Dickinson, Paul Milne, Dr Laura JardineORCiD, Dr Naomi McGovern, Dr Sharon Cookson, Sarah Pagan, Professor Andrew GenneryORCiD, Dr Eleonora Gambineri, Dr Christopher Bacon, Dr Sophie Hambleton, Professor Muzlifah Haniffa, Dr Venetia BigleyORCiD, Professor Matthew CollinORCiD


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Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56bright NK cells, na¨ıve T cells, and accumulation of terminally differentiated NK and CD81 memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.

Publication metadata

Author(s): Dickinson RE, Milne P, Jardine L, Zandi S, Swierczek SI, McGovern N, Cookson S, Ferozepurwalla Z, Langridge A, Pagan S, Gennery A, Heiskanen-Kosma T, Hamalainen S, Seppanen M, Helbert M, Tholouli E, Gambineri E, Reykdal S, Gottfreosson M, Thaventhiran JE, Morris E, Hirschfield G, Richter AG, Jolles S, Bacon CM, Hambleton S, Haniffa M, Bryceson Y, Allen C, Prchal JT, Dick JE, Bigley V, Collin M

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2014

Volume: 123

Issue: 6

Pages: 863-874

Print publication date: 06/02/2014

Online publication date: 17/12/2013

Acceptance date: 01/12/2013

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: The American Society of Hematology


DOI: 10.1182/blood-2013-07-517151

PubMed id: 24345756


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Funder referenceFunder name
Bright Red
British Society of Hematology
George Walker Trust
Lymphoma and Leukaemia Research
Wellcome Trust
101155/Z/13/ZWellcome Trust