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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, Professor 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.
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
URL: http://dx.doi.org/10.1182/blood-2013-07-517151
DOI: 10.1182/blood-2013-07-517151
PubMed id: 24345756
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