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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 (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 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 Rio, P. Articles by Bueren, J. A. Search for Related Content PubMed PubMed Citation Articles by Rio, P. Articles by Bueren, J. A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 12, 2008 Accepted August 29, 2008 In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1 Paula Rio, Nestor W. Meza, Africa Gonzalez-Murillo, Susana Navarro, Lara Alvarez, Jordi Surralles, Maria Castella, Guillermo Guenechea, Jose C. Segovia, Helmut Hanenberg, and Juan A. Bueren* Hematopoiesis and Gene Therapy Division, CIEMAT / CIBER-ER, Madrid, Spain LABIEMET, School of Medicine of Tachira, Universidad de los Andes, San Cristobal, Venezuela Department of Genetics and Microbiology, Universitat Autonoma de Barcelona and CIBER-ER, Barcelona, Spain Department of Pediatric Oncology, Hematology and Immunology, Children's Hospital, Duesseldorf, Germany * Corresponding author; email: juan.bueren{at}ciemat.es. 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 hematological status of the patient. In contrast to these observations, it is still unclear whether the ex vivo genetic correction of FA HSCs also provides a similar proliferation advantage to FA HSCs. Using a 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 this data, hematopoietic progenitors from FA recipients progressively became mitomycin C resistant and their chromosomal instability was reverted. No evidences of myelodysplasia, leukemias or abnormal clonal repopulation patterns were observed at multiple time points in primary or secondary recipients. Our results demonstrate that the 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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