Perturbed granulopoiesis in mice with a targeted mutation in the granulocyte colony-stimulating factor receptor gene associated with severe chronic neutropenia

Mutations in the granulocyte colony-stimulating factor (G-CSF) receptor gene are found in a number of patients with severe chronic neutropenia predisposed to acute myeloid leukemia. These mutations result in the absence of the C-terminal domain of the G-CSF-R, a region which has been implicated in differentiation signaling. We generated mice with an equivalent mutation (gcsfr-Delta 715) by homologous and Cre-mediated recombination in embryonic stem cells. Both wt/Delta 715 and Delta 715/Delta 715 mice have significantly reduced numbers of blood neutrophils compared with their wt/wtlittermates. However, under continuous G-CSF administration mutant mice develop peripheral neutrophil counts that significantly exceed those of wild-type littermates, These findings indicate that depending on G-CSF levels in mice, the Delta 715 mutation can contribute both to neutropenia and to neutrophilia. (C) 1998 by The American Society of Hematology.