Altered chemotactic response to CXCL12 in patients carrying GATA2 mutations

Abstract

GATA2 deficiency formerly described as MonoMAC syndrome; dendritic a cells, monocytes, B cells, and natural killer cell deficiency; familial a myelodysplastic syndrome/acute myeloid leukemia; or Emberger syndrome a encompasses a range of hematologic and nonhematologic anomalies, mainly a characterized by monocytopenia, B lymphopenia, natural killer cell a cytopenia, neutropenia, immunodeficiency, and a high risk of developing a acute myeloid leukemia. Herein, we present 7 patients with GATA2 a deficiency recruited into the French Severe Chronic Neutropenia a Registry, which enrolls patients with all kinds of congenital a neutropenia. We performed extended immunophenotyping of their whole a blood lymphocyte populations, together with the analysis of their a chemotactic responses. Lymphopenia was recorded for B and CD4(+) T cells a in 6 patients. Although only 3 patients displayed natural killer cell a cytopenia, the CD56(bright) natural killer subpopulation was nearly a absent in all 7 patients. Natural killer cells from 6 patients showed a decreased CXCL12/CXCR4-dependent chemotaxis, whereas other lymphocytes, a and most significantly B lymphocytes, displayed enhanced CXCL12induced a chemotaxis compared with healthy volunteers. Surface expression of CXCR4 a was significantly diminished in the patients' natural killer cells, a although the total expression of the receptor was found to be equivalent a to that of natural killer cells from healthy individual controls. a Together, these data reveal that GATA2 deficiency is associated with a impaired membrane expression and chemotactic dysfunctions of CXCR4. a These dysfunctions may contribute to the physiopathology of this a deficiency by affecting the normal distribution of lymphocytes and thus a potentially affecting the susceptibility of patients to associated a infections.