Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1.
We have investigated the hematopoietic phenotype of mice with a hypomorphic mutation in the Brca2/Fancd1 gene (Brca2(Delta27/Delta27) 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(Delta27/Delta27) mice, either young or adult. Additionally, a high incidence of spontaneous chromosomal instability was observed in Brca2(Delta27/Delta27) bone marrow (BM) cells, but not in Brca2(+/Delta27) or Fanca(-/-) BM cells. Although Brca2(Delta27/Delta27) CFCs were not hypersensitive to ionizing radiation, a very severe hematopoietic syndrome was observed in irradiated Brca2(Delta27/Delta27) mice. Conventional BM competition experiments showed a marked repopulation defect in Brca2(Delta27/Delta27) 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(Delta27/Delta27) HSCs maintained in their natural physiological environment. The progressive repopulation of wild-type HSCs transplanted into unconditioned Brca2(Delta27/Delta27) recipients is reminiscent of the somatic mosaicism phenomenon observed in a number of genetic diseases, including FA. The hematopoietic phenotype associated with the Brca2(Delta27/Delta27) mutation suggests that this FA-D1 mouse model will constitute an important tool for the development of new therapies for FA, including gene therapy.
Navarro
Susana
S
Hematopoiesis and Gene Therapy Division, CIEMAT/Marcelino Botín Foundation, Avenida Complutense No. 22, 28040 Madrid, Spain.
Meza
Nestor W
NW
Quintana-Bustamante
Oscar
O
Casado
José A
JA
Jacome
Ariana
A
McAllister
Kimberly
K
Puerto
Silvia
S
Surrallés
Jordi
J
Segovia
José C
JC
Bueren
Juan A
JA
D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation; D002869:Chromosome Aberrations / Q000139:chemically induced; D004195:Disease Models, Animal; D005199:Fanconi Anemia / Q000145:classification / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D017353:Gene Deletion; D018380:Hematopoietic Stem Cell Transplantation; D006413:Hematopoietic System / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016685:Mitomycin / Q000494:pharmacology; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype
D024682:BRCA2 Protein; C106711:BRCA2 protein, mouse; D016685:Mitomycin