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Blood, 15 September 2002, Vol. 100, No. 6, pp. 2032-2039
GENE THERAPY
In vitro phenotypic correction of hematopoietic progenitors
from Fanconi anemia group A knockout mice
Paula Río,
José Carlos Segovia,
Helmut Hanenberg,
José
Antonio Casado,
Jesús Martínez,
Kerstin Göttsche,
Ngan Ching Cheng,
Henri J. Van de
Vrugt,
Fré Arwert,
Hans Joenje, and
Juan A. Bueren
From the Hematopoietic Gene Therapy Program,
Centro de Investigaciones Energéticas,
Medioambientales y Tecnológicas (CIEMAT)/Marcelino
Botín Foundation, Madrid, Spain; the Department of Pediatric
Hematology and Oncology, Children's Hospital Heinrich Heine
University, Düsseldorf, Germany; and the Department of Clinical
Genetics and Human Genetics, Free University Medical Center, Amsterdam,
The Netherlands.
Fanconi anemia (FA) is a rare autosomal recessive disease,
characterized by bone marrow failure and cancer predisposition. So far, 8 complementation groups have been identified, although mutations in FANCA account for the disease in the majority
of FA patients. In this study we characterized the hematopoietic phenotype of a Fanca knockout mouse model and corrected the
main phenotypic characteristics of the bone marrow (BM)
progenitors using retroviral vectors. The hematopoiesis of these
animals was characterized by a modest though significant
thrombocytopenia, consistent with reduced numbers of BM megakaryocyte
progenitors. As observed in other FA models, the hematopoietic
progenitors from Fanca / mice were highly
sensitive to mitomycin C (MMC). In addition, we observed for the first
time in a FA mouse model a marked in vitro growth defect of
Fanca/ progenitors, either when total BM or
when purified LinSca-1+ cells were subjected
to in vitro stimulation. Liquid cultures of
Fanca/ BM that were stimulated with stem
cell factor plus interleukin-11 produced low numbers of
granulocyte macrophage colony-forming units, contained a high
proportion of apoptotic cells, and generated a decreased proportion of
granulocyte versus macrophage cells, compared to normal BM cultures.
Aiming to correct the phenotype of Fanca/
progenitors, purified LinSca-1+ cells
were transduced with retroviral vectors encoding the enhanced green
fluorescent protein (EGFP) gene and human FANCA
genes. LinSca-1+ cells from
Fanca/ mice were transduced with an
efficiency similar to that of samples from wild-type mice. More
significantly, transductions with FANCA vectors corrected
both the MMC hypersensitivity as well as the impaired ex vivo expansion
ability that characterized the BM progenitors of
Fanca/ mice.
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