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Prepublished online as a Blood First Edition Paper on December 5, 2002; DOI 10.1182/blood-2002-06-1656.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2570-2574
HEMATOPOIESIS
Role of the WT1 tumor suppressor in murine
hematopoiesis
Julia A. Alberta,
Gregory
M. Springett,
Helen Rayburn,
Thomas A. Natoli,
Janet Loring,
Jordan A. Kreidberg, and
David Housman
From the Center for Cancer Research, the Department of
Biology, and the Whitehead Institute, Massachusetts Institute of
Technology, Cambridge; the Department of Medicine, Children's
Hospital, Boston; and the Department of Pediatrics, Harvard Medical
School, Boston, MA.
The WT1 tumor-suppressor gene is
expressed by many forms of acute myeloid leukemia. Inhibition of this
expression can lead to the differentiation and reduced growth of
leukemia cells and cell lines, suggesting that WT1 participates in
regulating the proliferation of leukemic cells. However, the role of
WT1 in normal hematopoiesis is not well understood. To investigate this
question, we have used murine cells in which the WT1 gene
has been inactivated by homologous recombination. We have found that
cells lacking WT1 show deficits in hematopoietic stem cell function.
Embryonic stem cells lacking WT1, although contributing
efficiently to other organ systems, make only a minimal contribution to
the hematopoietic system in chimeras, indicating that hematopoietic
stem cells lacking WT1 compete poorly with healthy stem
cells. In addition, fetal liver cells lacking WT1 have an
approximately 75% reduction in erythroid blast-forming unit (BFU-E),
erythroid colony-forming unit (CFU-E), and colony-forming
unit-granulocyte macrophage-erythroid-megakaryocyte (CFU-GEMM).
However, transplantation of fetal liver hematopoietic cells lacking
WT1 will repopulate the hematopoietic system of an
irradiated adult recipient in the absence of competition. We conclude
that the absence of WT1 in hematopoietic cells leads to functional
defects in growth potential that may be of consequence to leukemic
cells that have alterations in the expression of WT1.
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