1. ¹Hematopoiesis and Gene Therapy Division, CIEMAT/Marcelino Botín Foundation, Avenida Complutense, No. 22, 28040 Madrid, Spain
2. ²National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD 20892, USA
3. ³Department of Genetics, Universitat Autonoma, 08193 Barcelona, Spain

Correspondence: Juan A. Bueren, Fax: +34 91 346 6484. E-mail: juan.bueren@ciemat.es

Received 27 January 2006; Revised 23 May 2006; Accepted 23 May 2006.

Abstract

We have investigated the hematopoietic phenotype of mice with a hypomorphic mutation in the Brca2/Fancd1 gene (Brca2^27/27 mutation). In contrast to observations made in other Fanconi anemia (FA) mouse models, low numbers of hematopoietic colony-forming cells (CFCs) were noted in Brca2^27/27 mice, either young or adult. Additionally, a high incidence of spontaneous chromosomal instability was observed in Brca2^27/27 bone marrow (BM) cells, but not in Brca2^+/27 or Fanca^-/- BM cells. Although Brca2^27/27 CFCs were not hypersensitive to ionizing radiation, a very severe hematopoietic syndrome was observed in irradiated Brca2^27/27 mice. Conventional BM competition experiments showed a marked repopulation defect in Brca2^27/27 hematopoietic stem cells (HSCs), compared to wild-type HSCs. Moreover, we have observed for the first time in a DNA repair disease model a very significant proliferation defect in Brca2^27/27 HSCs maintained in their natural physiological environment. The progressive repopulation of wild-type HSCs transplanted into unconditioned Brca2^27/27 recipients is reminiscent of the somatic mosaicism phenomenon observed in a number of genetic diseases, including FA. The hematopoietic phenotype associated with the Brca2^27/27 mutation suggests that this FA-D1 mouse model will constitute an important tool for the development of new therapies for FA, including gene therapy.