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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-08-2404. This Article Full Text (PDF) All Versions of this Article: 2002-08-2404v1 101/4/1299    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 Haneline, L. S Articles by Clapp, D. W. Search for Related Content PubMed PubMed Citation Articles by Haneline, L. S Articles by Clapp, D. W. Social Bookmarking                   What's this? Submitted August 8, 2002 Accepted September 26, 2002 Retroviral-mediated expression of recombinant Fancc enhances the repopulating ability of Fancc -/- hematopoietic stem cells and decreases the risk of clonal evolution Laura S Haneline*, Xiaxin Li, Samantha L M Ciccone, Ping Hong, Yanzhu Yang, Hal E Broxmeyer, Suk-Hee Lee, Attilio Orazi, Edward F Srour, and D. Wade Clapp Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, USA Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN, USA Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA Walther Cancer Institute, Indianapolis, IN, USA * Corresponding author; email: lhanelin{at}iupui.edu. Fanconi anemia (FA) is a chromosomal instability disorder characterized by a progressive bone marrow (BM) failure and an increased incidence of myeloid leukemias. Children with FA are currently being enrolled in clinical trials to evaluate the safety of retroviral-mediated gene transfer. Previously, we used Fancc -/- mice to show that Fancc -/- hematopoietic stem cells (HSC) have a profound defect in repopulating ability. Here, we examined whether retroviral-mediated gene transfer of recombinant Fancc (rFancc) would restore the repopulating ability of Fancc -/- HSC to wildtype levels. Fancc -/- HSC transduced with a retrovirus encoding rFancc exhibited a repopulating ability that approached wildtype levels. Interestingly, ~30% of primary recipients (7 of 22) transplanted with uncorrected Fancc -/- cells developed a range of hematopoietic abnormalities including pancytopenia and BM hypoplasia similar to individuals with FA. Hematopoietic abnormalities were detected in only 1 of 22 mice transplanted with Fancc -/- cells transduced with a retrovirus encoding rFancc. Moreover, several mice with hematopoietic defects had progenitors that displayed a marked resistance to IFN-, TNF-, and MIP-1 compared to both Fancc -/- progenitors, which are uniquely hypersensitive to these cytokines, and wildtype progenitors. These data are analogous to studies using progenitors from patients with myelodysplasia and provide functional support for clonal evolution in these mice. Collectively, these data show that gene transfer can enhance HSC repopulating ability and suppresses the tendency for clonal evolution. These studies also reveal potential detrimental effects of ex vivo manipulation for untransduced Fancc -/- HSC. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. D. Milsom, B. Schiedlmeier, J. Bailey, M.-O. Kim, D. Li, M. Jansen, A. M. Ali, M. Kirby, C. Baum, L. J. Fairbairn, et al. 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