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Blood, 15 January 2002, Vol. 99, No. 2, pp. 479-487
HEMATOPOIESIS
Reduced lymphomyeloid repopulating activity from adult bone
marrow and fetal liver of mice lacking expression of STAT5
Kevin D. Bunting,
Heath L. Bradley,
Teresa S. Hawley,
Richard Moriggl,
Brian P. Sorrentino, and
James
N. Ihle
From the Hematopoiesis Department, American Red
Cross Holland Laboratory, Rockville, MD; the Research Institute
of Molecular Pathology, Vienna, Austria; the Division of Experimental
Hematology and the Biochemistry Department, St Jude Children's
Research Hospital, Memphis, TN; and the Howard Hughes Medical
Institute, Chevy Chase, MD.
Signal transducers and activators of transcription (STATs) are
intracellular mediators of cytokine receptor signals. Because many
early-acting growth factors have been implicated in STAT5 activation,
this study sought to investigate whether STAT5 may be a transcriptional
regulator of hematopoietic stem cell (HSC) long-term repopulating
activity. To test this possibility, bone marrow (BM) and fetal liver
(FL) cells from mice containing homozygous deletions of both STAT5a and
STAT5b genes (STAT5ab /) were characterized for
hematopoietic repopulating activities. BM and FL grafts were capable of
repopulating lymphoid and myeloid lineages of lethally irradiated
primary and secondary hosts, with defects observed primarily in
T-lymphocyte engraftment. Because only a fraction of normal HSC
function is required to reconstitute hematopoiesis, competitive
repopulation assays of adult BM or FL cells were used against wild type
adult BM or FL cells to quantitate stem cell function. In these
analyses, average 25-, 28-, 45-, and 68-fold decreases in normal
repopulating activity were evident in granulocyte (Gr-1+),
macrophage (Mac-1+), erythroid progenitor
(Ter119+), and B-lymphocyte (B220+)
populations, respectively, with T lymphocytes (CD4+) always
undetectable from the STAT5ab/ graft. Consistent with
previous reports of divergence between stem cell phenotype and function
in cases of perturbed hematopoiesis, the absolute number of cells
within Sca-1+c-kit+lin or
lin Hoechst 33342 side population fractions was not
significantly different between wild type and STAT5ab/
BM or FL cells. These results demonstrate that a significant proportion
of the growth factor signals required for multilineage reconstitution
potential of HSCs is STAT5 dependent.
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