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Bone Marrow Failure in the Fanconi Anemia Group C Mouse Model
After DNA Damage
Madeleine Carreau,
Olga I. Gan,
Lili Liu,
Monica Doedens,
Colin McKerlie,
John E. Dick, and
Manuel Buchwald
From the Department of Genetics, Research Institute, Hospital for
Sick Children, Toronto, Ontario, Canada; Research Services and
Pathology, Sunnybrook Health Science Centre, University of Toronto,
North York, Ontario, Canada; and the Department of Molecular and
Medical Genetics, University of Toronto, Toronto, Ontario, Canada.
Fanconi anemia (FA) is a pleiotropic inherited disease that causes
bone marrow failure in children. However, the specific involvement of
FA genes in hematopoiesis and their relation to bone marrow (BM)
failure is still unclear. The increased sensitivity of FA cells to DNA
cross-linking agents such as mitomycin C (MMC) and diepoxybutane (DEB),
including the induction of chromosomal aberrations and delay in the G2
phase of the cell cycle, have suggested a role for the FA genes in DNA
repair, cell cycle regulation, and apoptosis. We previously reported
the cloning of the FA group C gene (FAC) and the generation of
a Fac mouse model. Surprisingly, the Fac  / mice
did not show any of the hematologic defects found in FA patients. To
better understand the relationship of FA gene functions to BM failure,
we have analyzed the in vivo effect of an FA-specific DNA damaging
agent in Fac / mice. The mice were found to be highly
sensitive to DNA cross-linking agents; acute exposure to MMC produced a
marked BM hypoplasia and degeneration of proliferative tissues and
caused death within a few days of treatment. However, sequential,
nonlethal doses of MMC caused a progressive decrease in all peripheral
blood parameters of Fac / mice. This treatment targeted
specifically the BM compartment, with no effect on other proliferative
tissues. The progressive pancytopenia resulted from a reduction in the
number of early and committed hematopoietic progenitors. These results
indicate that the FA genes are involved in the physiologic response of hematopoietic progenitor cells to DNA damage.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2737-2744
© 1998 by The American Society of Hematology.
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