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Genetic influences determining progenitor cell mobilization and
leukocytosis induced by granulocyte colony-stimulating factor
AW Roberts, S Foote, WS Alexander, C Scott, L Robb and D Metcalf
The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne
Hospital, Victoria, Australia.
The mechanisms involved in the mobilization of progenitor cells into the
blood by granulocyte colony-stimulating factor (G-CSF) and other cytokines
are poorly understood. To identify important influences on this complex
process, in vivo murine models were used. Granulocyte- macrophage
colony-stimulating factor (GM-CSF) transgenic, Max41 transgenic, W/Wv,
Mpl-null, GM-CSF receptor (beta chain)-null mice, wild-type littermate
controls, and six inbred strains of mice were injected with 200 microg/kg/d
G-CSF for 5 days. Three parameters of response were monitored: white blood
cell count (WCC), peripheral blood progenitor cell (PBPC) numbers, and
spleen weight. In all genotypes studied, G-CSF induced increases in these
three parameters. However, PBPC mobilization in W/Wv and Mpl-null mice was
only 30% and 9%, respectively, of that observed in wild-type mice. In
contrast, perturbations of GM-CSF signalling had no demonstrable effect on
in vivo responses to G-CSF. Broad variability was evident between inbred
strains for each parameter of the response to G-CSF. A 10-fold range in
response was observed for circulating progenitor cell numbers, similar to
that observed for normal human subjects receiving G-CSF. The interstrain
differences were in the distribution of mature and progenitor cells between
peripheral blood, bone 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 and intermediate-responding SJL mice indicated that regulation of
progenitor cell mobilization is a complex genetic trait, that there is a
correlation between this trait and WCC response (r2 = .5), and that this
approach may serve as a useful model for the identification of genes
involved in the mobilization process.
Volume 89,
Issue 8,
pp. 2736-2744,
04/15/1997
Copyright © 1997 by The American Society of Hematology
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