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Blood, 15 August 2001, Vol. 98, No. 4, pp. 1003-1011
HEMATOPOIESIS
Defective hematopoiesis and hepatic steatosis in mice with
combined deficiencies of the genes encoding Fancc and Cu/Zn
superoxide dismutase
Suzana Hadjur,
Karen Ung,
Louis Wadsworth,
James Dimmick,
Evica Rajcan-Separovic,
Richard W. Scott,
Manuel Buchwald, and
Frank R. Jirik
From the Centre for Molecular Medicine and
Therapeutics, and the Departments of Medicine and Pathology, British
Columbia Research Institute for Children's and Women's Health,
University of British Columbia, Vancouver, British Columbia, Canada;
Cephalon Incorporated, West Chester, Pennsylvania; and Genetics and
Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Several lines of evidence point to an abnormality in the response
of Fanconi anemia cells to reactive oxygen species. To investigate the
potential pathologic consequences of an in vivo alteration of redox
state in mice lacking one of the Fanconi anemia genes, animals were
generated having combined deficiencies of the cytosolic Cu/Zn
superoxide dismutase (Sod1) and Fanconi anemia
complementation group C (Fancc) genes. Interestingly,
hepatocytes of Fancc /Sod1/
mice exhibited a zonal pattern of microvesicular steatosis,
possibly as a result of oxidative stress-induced injury to hepatocyte
membranes. Consistent with this idea, freshly explanted
Fancc/Sod1/ hepatocytes
demonstrated increased spontaneous production of superoxide in vitro.
The second phenotypic feature of
Fancc/ Sod1/ mice
was that of bone marrow hypocellularity accompanied by significant decreases in peripheral blood erythrocyte and leukocyte numbers as
compared with wild-type controls. Although flow cytometry analysis with
monoclonal antibodies against cell surface antigens revealed normal
numbers of primitive hematopoietic progenitor populations in
Fancc/Sod1/ marrow,
lineage-positive progenitor numbers were significantly reduced in
these mice. Furthermore, the in vitro clonogenic growth of
Fancc/Sod1/ erythroid,
myeloid, and early B-lymphoid colonies in semisolid media was
profoundly compromised. These results suggested that the altered redox
state likely present in
Fancc/ Sod1/
hematopoietic progenitors was responsible for an impairment of cell proliferation or survival.
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