In vivo selection of wild-type hematopoietic stem cells in a murine model of Fanconi anemia

• Published in: Blood 1999-09, Vol.94 (6), p.2151-2158
• Main Authors: BATTAILE, K. P, BATEMAN, R. L, MORTIMER, D, MULCAHY, J, RATHBUN, R. K, BAGBY, G, FLEMING, W. H, GROMPE, M
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Bone Marrow Cells - cytology; Bone Marrow Cells - pathology; Bone Marrow Transplantation; Bone marrow, stem cells transplantation. Graft versus host reaction; Fanconi Anemia - genetics; Fanconi Anemia - pathology; Fanconi Anemia - therapy; Genotype; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - pathology; Medical sciences; Mice; Mice, Knockout; Mitomycin - pharmacology; Polymerase Chain Reaction; Transfusions. Complications. Transfusion reactions. Cell and gene therapy
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.v94.6.2151

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.