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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 700-704
Phenotypic correction of Fanconi anemia group C knockout mice
Kimberly A. Gush,
Kai-Ling Fu,
Markus Grompe, and
Christopher E. Walsh
From the UNC Gene Therapy Center and the Department of Medicine,
University of North Carolina, Chapel Hill, NC; and the
Department of Genetics, Oregon Health Sciences Center, Portland,
OR.
Fanconi anemia (FA) is a genetic disorder characterized by bone
marrow failure, congenital anomalies, and a predisposition to
malignancy. FA cells demonstrate hypersensitivity to DNA cross-linking agents, such as mitomycin C (MMC). Mice with a targeted disruption of
the FANCC gene (fancc  / nullizygous mice)
exhibit many of the characteristic features
of FA and provide a valuable tool for testing novel therapeutic
strategies. We have exploited the inherent hypersensitivity of
fancc / hematopoietic cells to assay for phenotypic
correction following transfer of the FANCC complementary DNA (cDNA)
into bone marrow cells. Murine fancc / bone marrow cells
were transduced with the use of retrovirus carrying the human
fancc cDNA and injected into lethally irradiated recipients.
Mitomycin C (MMC) dosing, known to induce pancytopenia, was used to
challenge the transplanted animals. Phenotypic correction was
determined by assessment of peripheral blood counts. Mice that received
cells transduced with virus carrying the wild-type gene maintained
normal blood counts following MMC administration. All nullizygous
control animals receiving MMC exhibited pancytopenia shortly before
death. Clonogenic assay and polymerase chain reaction analysis
confirmed gene transfer of progenitor cells. These results indicate
that selective pressure promotes in vivo enrichment of fancc-transduced hematopoietic stem/progenitor cells. In
addition, MMC resistance coupled with detection of the transgene in
secondary recipients suggests transduction and phenotypic correction of long-term repopulating stem cells.
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