PERTURBED GRANULOPOIESIS IN MICE WITH A TARGETED MUTATION IN THE GRANULOCYTE-COLONY-STIMULATING FACTOR-RECEPTOR GENE ASSOCIATED WITH SEVERECHRONIC NEUTROPENIA

Mutations in the granulocyte colony-stimulating factor (G-CSF) recepto r gene are found in a number of patients with severe chronic neutropen ia predisposed to acute myeloid leukemia. These mutations result in th e absence of the C-terminal domain of the G-CSF-R, a region which has been implicated in differentiation signaling. We generated mice with a n equivalent mutation (gcsfr-Delta 715) by homologous and Cre-mediated recombination in embryonic stem cells. Both wt/Delta 715 and Delta 71 5/Delta 715 mice have significantly reduced numbers of blood neutrophi ls compared with their wt/wtlittermates. However, under continuous G-C SF administration mutant mice develop peripheral neutrophil counts tha t significantly exceed those of wild-type littermates, These findings indicate that depending on G-CSF levels in mice, the Delta 715 mutatio n can contribute both to neutropenia and to neutrophilia. (C) 1998 by The American Society of Hematology.