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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 2151-2158
In Vivo Selection of Wild-Type Hematopoietic Stem Cells in a Murine
Model of Fanconi Anemia
Kevin P. Battaile,
Raynard L. Bateman,
Derik Mortimer,
Jean Mulcahy,
R. Keaney Rathbun,
Grover Bagby,
William H. Fleming, and
Markus Grompe
From the Department of Molecular and Medical Genetics and the
Division of Hematology and Medical Oncology, Oregon Health Sciences
University, Portland, OR; and the Portland Veterans Affairs Medical
Center, Portland, OR.
Fanconi anemia (FA) is an autosomal recessive disorder characterized
by birth defects, increased incidence of malignancy, and progressive
bone marrow failure. Bone marrow transplantation is therapeutic and,
therefore, FA is a candidate disease for hematopoietic gene therapy.
The frequent finding of somatic mosaicism in blood of FA patients has
raised the question of whether wild-type bone marrow may have a
selective growth advantage. To test this hypothesis, a cohort
radio-ablated wild-type mice were transplanted with a 1:1 mixture of FA
group C knockout (FACKO) and wild-type bone marrow. Analysis of
peripheral blood at 1 month posttransplantation showed only a moderate
advantage for wild-type cells, but upon serial transplantation, clear
selection was observed. Next, a cohort of FACKO mice received a
transplant of wild-type marrow cells without prior
radio-ablation. No wild-type cells were detected in peripheral blood
after transplantation, but a single injection of mitomycin C (MMC)
resulted in an increase to greater than 25% of wild-type DNA. Serial
transplantation showed that the selection occurred at the level of
hematopoietic stem cells. No systemic side effects were observed. Our
results show that in vivo selection for wild-type hematopoietic stem
cells occurs in FA and that it is enhanced by MMC administration.
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