title: The evolution of cellular deficiency in GATA2 mutation.
abstract: 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, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Dickinson
authors.forename: Paul
authors.initials: P
authors.lastname: Milne
authors.forename: Laura
authors.initials: L
authors.lastname: Jardine
authors.forename: Sasan
authors.initials: S
authors.lastname: Zandi
authors.forename: Sabina I
authors.initials: SI
authors.lastname: Swierczek
authors.forename: Naomi
authors.initials: N
authors.lastname: McGovern
authors.forename: Sharon
authors.initials: S
authors.lastname: Cookson
authors.forename: Zaveyna
authors.initials: Z
authors.lastname: Ferozepurwalla
authors.forename: Alexander
authors.initials: A
authors.lastname: Langridge
authors.forename: Sarah
authors.initials: S
authors.lastname: Pagan
authors.forename: Andrew
authors.initials: A
authors.lastname: Gennery
authors.forename: Tarja
authors.initials: T
authors.lastname: Heiskanen-Kosma
authors.forename: Sari
authors.initials: S
authors.lastname: Hämäläinen
authors.forename: Mikko
authors.initials: M
authors.lastname: Seppänen
authors.forename: Matthew
authors.initials: M
authors.lastname: Helbert
authors.forename: Eleni
authors.initials: E
authors.lastname: Tholouli
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gambineri
authors.forename: Sigrún
authors.initials: S
authors.lastname: Reykdal
authors.forename: Magnús
authors.initials: M
authors.lastname: Gottfreðsson
authors.forename: James E
authors.initials: JE
authors.lastname: Thaventhiran
authors.forename: Emma
authors.initials: E
authors.lastname: Morris
authors.forename: Gideon
authors.initials: G
authors.lastname: Hirschfield
authors.forename: Alex G
authors.initials: AG
authors.lastname: Richter
authors.forename: Stephen
authors.initials: S
authors.lastname: Jolles
authors.forename: Chris M
authors.initials: CM
authors.lastname: Bacon
authors.forename: Sophie
authors.initials: S
authors.lastname: Hambleton
authors.forename: Muzlifah
authors.initials: M
authors.lastname: Haniffa
authors.forename: Yenan
authors.initials: Y
authors.lastname: Bryceson
authors.forename: Carl
authors.initials: C
authors.lastname: Allen
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.forename: Venetia
authors.initials: V
authors.lastname: Bigley
authors.forename: Matthew
authors.initials: M
authors.lastname: Collin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D060965:Clonal Evolution; D003430:Cross-Sectional Studies; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D050989:GATA2 Transcription Factor / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000235:genetics / Q000473:pathology*; D010375:Pedigree; D011379:Prognosis; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3