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Blood, 1 June 2002, Vol. 99, No. 11, pp. 3947-3954
HEMATOPOIESIS
Genetically determined variation in the number of phenotypically
defined hematopoietic progenitor and stem cells and in their
response to early-acting cytokines
Els Henckaerts,
Hartmut Geiger,
Jessica C. Langer,
Patricia Rebollo,
Gary Van Zant, and
Hans-Willem Snoeck
From the Carl C. Icahn Institute for Gene Therapy and
Molecular Medicine, Mount Sinai School of Medicine, New York, NY; and
the Markey Cancer Center, University of Kentucky, Lexington.
Quantitative trait analysis may shed light on mechanisms regulating
hematopoiesis in vivo. Strain-dependent variation existed among C57BL/6
(B6), DBA/2, and BXD recombinant inbred mice in the responsiveness of
primitive progenitor cells to the early-acting cytokines kit ligand,
flt3 ligand, and thrombopoietin. A significant quantitative trait locus
was found on chromosome 2 that could not be confirmed in congenic mice,
however, probably because of epistasis. Because it has been shown that
alleles of unknown X-linked genes confer a selective advantage to
hematopoietic stem cells in vivo in humans and in cats, we also
analyzed reciprocal male D2B6F1 and B6D2F1 mice, revealing an X-linked
locus regulating the responsiveness of progenitor and stem cells to
early-acting factors. Among DBA/2, B6, and BXD recombinant inbred mice,
correlating genetic variation was found in the absolute number and
frequency of Lin Sca1++kit+ cells,
which are highly enriched in hematopoietic progenitor and stem cells,
and in the number of
LinSca1++kit cells, a
population whose biologic significance is unknown, suggesting that both
populations are functionally related. Suggestive quantitative trait
loci (QTLs) for the number of
LinSca1++ cells on chromosomes 2, 4, and 7 were confirmed in successive rounds of mapping. The locus on chromosome
2 was confirmed in congenic mice. We thus demonstrated genetic
variation in the response to cytokines critical for hematopoiesis in
vivo and in the pool size of cells belonging to a phenotype used to
isolate essentially pure primitive progenitor and stem cells, and we
identified loci that may be relevant to the regulation of hematopoiesis
in steady state.
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