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Blood, 15 December 2008, Vol. 112, No. 13, pp. 4853-4861. Prepublished online as a Blood First Edition Paper on September 23, 2008; DOI 10.1182/blood-2008-05-156356. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-05-156356v1 112/13/4853    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Río, P. Articles by Bueren, J. A. Search for Related Content PubMed PubMed Citation Articles by Río, P. Articles by Bueren, J. A. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1 Paula Río1, Néstor W. Meza1,2, África González-Murillo1, Susana Navarro1, Lara Álvarez1, Jordi Surrallés3, Maria Castella3, Guillermo Guenechea1, José C. Segovia1, Helmut Hanenberg4,5, and Juan A. Bueren1 1 Hematopoiesis and Gene Therapy Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain; 2 Laboratorio Integrado de la Escuela de Medicina en el Táchira (LABIEMET), School of Medicine of Táchira, Universidad de los Andes, San Cristóbal, Venezuela; 3 Department of Genetics and Microbiology, Universitat Autónoma de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras, Bellaterra, Barcelona, Spain; 4 Department of Pediatric Oncology, Hematology and Immunology, Children's Hospital, Dusseldorf, Germany; and 5 Department of Pediatrics, Wells Center for Pediatric Research, Riley Hospital for Children, Indianapolis, IN Fanconi anemia (FA) is an inherited recessive DNA repair disorder mainly characterized by bone marrow failure and cancer predisposition. Studies in mosaic FA patients have shown that reversion of one inherited germ-line mutation resulting in a functional allele in one or a few hematopoietic stem cells (HSCs) can lead to the proliferation advantage of corrected cells, thus over time normalizing the hematologic status of the patient. In contrast to these observations, it is still unclear whether ex vivo genetic correction of FA HSCs also provides a similar proliferation advantage to FA HSCs. Using an FA mouse model with a marked hematopoietic phenotype, the FA-D1 (Brca227/27) mice, we demonstrate that the lentivirus-mediated gene therapy of FA HSCs results in the progressive expansion of genetically corrected clones in mild-conditioned FA-D1 recipients. Consistent with these data, hematopoietic progenitors from FA recipients progressively became mitomycin C resistant and their chromosomal instability was reverted. No evidence of myelodysplasia, leukemias, or abnormal clonal repopulation was observed at multiple time points in primary or secondary recipients. Our results demonstrate that ectopic expression of BRCA2 confers a beneficial in vivo proliferation advantage to FA-D1 HSCs that enables the full hematopoietic repopulation of FA recipients with genetically corrected cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: I. D. Rosa, S. Goffart, M. Wurm, C. Wiek, F. Essmann, S. Sobek, P. Schroeder, H. Zhang, J. Krutmann, H. Hanenberg, et al. Adaptation of topoisomerase I paralogs to nuclear and mitochondrial DNA Nucleic Acids Res., October 1, 2009; 37(19): 6414 - 6428. [Abstract] [Full Text] [PDF]

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