Abnormal responsiveness of granulocyte-committed progenitor cells in cyclic neutropenia

The mechanism(s) driving cyclic hematopoiesis in human cyclic neutropenia remains unknown. Clinical trials suggest that an abnormal responsiveness of bone marrow progenitor cells to hematopoietic growth factors might cause oscillatory blood counts. Studies were performed to determine whether an abnormal responsiveness to multiple growth factors exists in this disorder and whether the defect could be shown in highly enriched populations of marrow progenitor cells. Bone marrow mononuclear cells from patients with congenital cyclic neutropenia required higher concentrations of added granulocyte-colony-stimulating factor (G-CSF) to achieve half-maximal colony growth than cells from normal subjects (478 +/- 90 pmol/L v 53 +/- 12 pmol/L, P less than .01). Patients also differed in requirement for granulocyte-macrophage-CSF (P less than .05), but not for interleukin-3 (P greater than .30). CD34+ bone marrow cells from three patients also showed this difference in G-CSF responsiveness (P less than .05). These data suggest that the defect in congenital cyclic hematopoiesis lies in growth factor receptor binding or the postreceptor signal transduction system that drives granulocytopoiesis.