GENETIC INFLUENCES DETERMINING PROGENITOR-CELL MOBILIZATION AND LEUKOCYTOSIS INDUCED BY GRANULOCYTE-COLONY-STIMULATING FACTOR

The mechanisms involved in the mobilization of progenitor cells into t he blood by granulocyte colony-stimulating factor (G-CSF) and other cy tokines are poorly understood. To identify important influences on thi s complex process, in vivo murine models were used. Granulocyte-macrop hage colony-stimulating factor (GM-CSF) transgenic, Max41 transgenic, W/W-V, Mpl-null, GM-CSF receptor (beta chain)-null mice, wild-type lit termate controls, and six inbred strains of mice were injected with 20 0 mu g/kg/d G-CSF for 5 days. Three parameters of response were monito red: white blood cell count (WCC), peripheral blood progenitor cell (P BPC) numbers, and spleen weight. In all genotypes studied, G-GSF induc ed increases in these three parameters. However, PBPC mobilization in W/W-V and Mpl-null mice was only 30% and 9%, respectively, of that obs erved in wild-type mice. in contrast, perturbations of GM-CSF signalli ng had no demonstrable effect on in vivo responses to G-CSF. Broad var iability was evident between inbred strains for each parameter of the response to G-CSF. A 10-fold range in response was observed for circul ating progenitor;cell numbers, similar to that observed for normal hum an subjects receiving G-CSF. The interstrain differences were in the d istribution of mature and progenitor cells between peripheral blood, b one marrow, and spleen rather than in the total numbers of these cells in the body. Results of an F2 intercross of low-responding C57BL/6 an d intermediate-responding SJL mice indicated that regulation of progen itor cell mobilization is a complex genetic trait, that there is a cor relation between this trait and WCC response (r(2) = .5), and that thi s approach may serve as a useful model for the identification of genes involved in the mobilization process. (C) 1997 by The American Societ y of Hematology.