The evolution of cellular deficiency in GATA2 mutation - PubMed (original) (raw)

Comparative Study

. 2014 Feb 6;123(6):863-74.

doi: 10.1182/blood-2013-07-517151. Epub 2013 Dec 17.

Paul Milne, Laura Jardine, Sasan Zandi, Sabina I Swierczek, Naomi McGovern, Sharon Cookson, Zaveyna Ferozepurwalla, Alexander Langridge, Sarah Pagan, Andrew Gennery, Tarja Heiskanen-Kosma, Sari Hämäläinen, Mikko Seppänen, Matthew Helbert, Eleni Tholouli, Eleonora Gambineri, Sigrún Reykdal, Magnús Gottfreðsson, James E Thaventhiran, Emma Morris, Gideon Hirschfield, Alex G Richter, Stephen Jolles, Chris M Bacon, Sophie Hambleton, Muzlifah Haniffa, Yenan Bryceson, Carl Allen, Josef T Prchal, John E Dick, Venetia Bigley, Matthew Collin

Affiliations

Comparative Study

The evolution of cellular deficiency in GATA2 mutation

Rachel E Dickinson et al. Blood. 2014.

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.

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Figures

Figure 1

Figure 1

Mononuclear cell profiles of patients with Emberger syndrome, monoMAC, and familial MDS associated with GATA2 mutation. Examples of mononuclear profiling in familial MDS (#18; T354M), monoMAC (#25; del340-381), and Emberger syndrome (#30; A341fs) showing that a DCML-deficiency phenotype may be associated with diverse clinical manifestations and different GATA2 mutations. Populations: (1) CD14+ monocyte; (2) CD16+ monocyte; (3) pDC; (4) CD34+ progenitors; (5) CD141+ mDC; (6) CD1c+ mDC; (7) B cells; and (8) NK cells. Note expansion of CD34+ progenitors.

Figure 2

Figure 2

Comparison of _GATA2_-mutated patients with MDS patients and genotype-phenotype correlations. (A-D) Comparison of controls (n = 21), patients with MDS (n = 12), and patients with symptomatic GATA2 mutation (n = 18). (A) Automated blood counts. (B-D) DCs, monocytes, and lymphocyte subsets by Trucount analysis. Analysis was performed as previously described. (E) Summary of clinical features among symptomatic carriers of GATA2 mutation by genotype (11 frameshift and 13 substitutions). (F) Profile of clinical score as defined in Table 1 according to genotype. (G) Age at presentation by genotype. *P < .05; **P < .01; ***P < .001. C, controls (or reference range); HPV, human papilloma virus; mono, monocyte; PAP, pulmonary alveolar proteinosis; URTI, upper respiratory tract infection.

Figure 3

Figure 3

Asymptomatic carriers of GATA2 mutation may develop cellular deficiency, elevated Flt3L, loss of BM progenitors, and clonal myelopoeisis. (A) Three pedigrees identified (mutation indicated) containing asymptomatic relatives (clinical core = 0), carrying GATA2 mutation (open symbols, arrowed). Gray symbols identify 2 patients with either elevated Flt3L (>200 pg/ml) or cytopenia. Filled symbols indicate affected patients with mutation (clinical score = 1 to 4). (B) DC, monocyte, and lymphocyte profiles of patient #5, 1 of 3 healthy carriers of GATA2 mutation showing a normal cellular phenotype at the first point of analysis in 2010. Populations: (1) CD14+ monocyte; (2) CD16+ monocyte; (3) pDC; (4) CD34+ progenitors; (5) CD141+ mDC; (6) CD1c+ mDC; (7) B cell; (8) T cell; and (9) NK cell. (C) Summary of DC and monocyte counts relative to reference ranges for the asymptomatic carriers. Case #5 (filled circle) is shown at first analysis in 2010. Case #21 (filled square) already has cytopenia. (D) Detailed analysis of case #5 showing the loss of cells and rising Flt3L over a 3-year period. (E) BM analysis of case #5 showing loss of B, NK, MLP, and GMP progenitors at midpoint when no cytopenia was evident. CMP, common myeloid progenitor; MEP, megakaryocyte-erythroid progenitor; MPP, multi-potent progenitor. (F) Pattern of X inactivation in females with GATA2 mutation at different stages of clinical evolution. Dominance of >75% is considered evidence of clonal hematopoiesis.

Figure 4

Figure 4

Flt3L is a specific marker of GATA2 mutation. (A) Flt3L was measured by ELISA in the serum of unaffected relatives with WT GATA2 (n = 13), individuals with GATA2 mutation (n = 24), patients with other PID (n = 11), and MDS patients (n = 11). For patients with GATA2 mutation, the clinical score (0 or 1 to 4) is indicated. (B) The relationship between Flt3L and the development of MDS (n = 24). (C) Relationship between Flt3L and clinical score, excluding patients with MDS (n = 18). (D) Decline in DCs/monocytes, B cells, and NK cells with increasing clinical score (n = 24). (E) Relationship between cell counts, Flt3L, and clinical stage (n = 24; shaded regions indicate normal ranges and asterisks indicate P values for Spearman correlation coefficients). (F) Elevation of Flt3L mRNA detected by Q-PCR in GATA2 patients compared with controls, and relationship between serum Flt-3L and percentage of CD3 (ie, T cells in PBMCs). *P < .05; **P < .01; ***P < .001. Q-PCR, quantitative polymerase chain reaction.

Figure 5

Figure 5

Highly differentiated phenotype of the peripheral lymphoid compartment of patients with GATA2 mutation. (A) Example of B-cell profile of patient with GATA2 mutation compared with control according to published descriptions., Populations: (1) transitional; (2) naïve mature; (3) mature activated; (4) resting memory; (5) plasmablast; and (6) CD38−CD21− (autoimmune-associated). (B) Quantification of _GATA2_-mutated patients vs controls showing depletion of transitional B cells and naïve memory B cells, and accumulation of memory B cells and CD38−CD21− B cells. (C) Example of NK-cell profile of patient with GATA2 mutation compared with control showing the distribution of CD56bright NK cells, and NKG2A+ and KIR+ cells within the CD56dim population. (D) Quantification of _GATA2_-mutated patients vs controls showing CD56bright NK cells and the expression of differentiation-associated antigens within the CD56dim population. Cytomegalovirus seropositivity is indicated by open symbols. (E) Example of CD3+ T-cell profile of a patient with GATA2 mutation compared with control showing CD4:CD8 profile and differentiation according to expression of CCR7 and CD45RA. (F) Quantification of antigen expression by CD8+ T cells of _GATA2_-mutated patients vs controls showing the acquisition of a terminally differentiated phenotype and increased expression of KIR on the CD56+ subset. (G) CD8+ CD161+ Va7.2+ MAIT cells are decreased in patients relative to controls. *P < .05; **P < .01; ***P < .001.

Figure 6

Figure 6

Schematic diagram summarizing the evolution of cellular deficiency in GATA2 mutation. BM MLPs are rapidly lost even in healthy carriers (see Figure 2). Peripheral blood CD34 counts are elevated in many patients (see examples in Figures 1 and 2) and tend to decline with advancing disease (not shown). Flt3L is progressively elevated, but declines as patients develop MDS (see Figure 4). A rapid rise in CD34+ cells and decline in Flt3L may signify the onset of MDS or AML, although AML may occur sporadically without prior cytopenia.

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