Altered chemotactic response to CXCL12 in patients carrying GATA2 mutations

Abstract

GATA2 deficiency-formerly described as MonoMAC syndrome; dendritic cells, monocytes, B cells, and natural killer cell deficiency; familial myelodysplastic syndrome/acute myeloid leukemia; or Emberger syndrome-encompasses a range of hematologic and nonhematologic anomalies, mainly characterized by monocytopenia, B lymphopenia, natural killer cell cytopenia, neutropenia, immunodeficiency, and a high risk of developing acute myeloid leukemia. Herein, we present 7 patients with GATA2 deficiency recruited into the French Severe Chronic Neutropenia Registry, which enrolls patients with all kinds of congenital neutropenia. We performed extended immunophenotyping of their whole blood lymphocyte populations, together with the analysis of their chemotactic responses. Lymphopenia was recorded for B and CD4(+) T cells in 6 patients. Although only 3 patients displayed natural killer cell cytopenia, the CD56(bright) natural killer subpopulation was nearly absent in all 7 patients. Natural killer cells from 6 patients showed decreased CXCL12/CXCR4-dependent chemotaxis, whereas other lymphocytes, and most significantly B lymphocytes, displayed enhanced CXCL12-induced chemotaxis compared with healthy volunteers. Surface expression of CXCR4 was significantly diminished in the patients' natural killer cells, although the total expression of the receptor was found to be equivalent to that of natural killer cells from healthy individual controls. Together, these data reveal that GATA2 deficiency is associated with impaired membrane expression and chemotactic dysfunctions of CXCR4. These dysfunctions may contribute to the physiopathology of this deficiency by affecting the normal distribution of lymphocytes and thus potentially affecting the susceptibility of patients to associated infections.

Genetic Causes of Human NK Cell Deficiency and Their Effect on NK Cell Subsets

“…Despite the presence of NK cells in some patients, a consistent and notable feature of GATA2 deficiency is the absolute loss of the CD56 bright NK cell subset (33). Originally described in a cohort of eight patients, this has since been reported by other groups (37, 38) and is a consistent feature of the >30 patients that we have studied with GATA2 deficiency and accompanying infectious history or hematologic disease.…”

“…The use of multiparametric flow cytometry to evaluate even the most rudimentary of NK cell subsets provides invaluable insight into the potential source of NKD. This is particularly true of GATA2 deficiency, which has a distinctive and seemingly immutable phenotype with regards to the absence of CD56 bright NK cells (33, 37, 38). …”

Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

“…bright NK cells, as previously described, 1,16,30 whereas asymptomatic carriers maintained these cells ( Figure 1B; supplemental Tables 1 and 2). Of note, 4 of 6 GATA2-mutated patients and asymptomatic carriers retaining CD3…”

Acquired Senescent T-Cell Phenotype Correlates with Clinical Severity in GATA Binding Protein 2-Deficient Patients

“…Moreover, percentage and absolute counts of NK cells (CD3 − CD56 + ) were markedly decreased (Figure 3A) with a seemingly total absence of the CD56 bright subset as previously described (8). In addition, the NKT population (CD3 + CD56 + ) was significantly increased in all patients (15). Patient 3 exhibited an extremely elevated percentage of NKT cells, with an NKT frequency of 68.26 ± 11.15% of total CD45 + lymphocytes (Figure 3B).…”