Altered chemotactic response to CXCL12 in patients carrying GATA2 ă mutations

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