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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4235-4246. Prepublished online as a Blood First Edition Paper on February 15, 2005; DOI 10.1182/blood-2004-11-4535. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-11-4535v1 105/11/4235    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 Modlich, U. Articles by Baum, C. Search for Related Content PubMed PubMed Citation Articles by Modlich, U. Articles by Baum, C. Related Collections Neoplasia Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Leukemias following retroviral transfer of multidrug resistance 1 (MDR1) are driven by combinatorial insertional mutagenesis Ute Modlich, Olga S. Kustikova, Manfred Schmidt, Cornelia Rudolph, Johann Meyer, Zhixiong Li, Kenji Kamino, Nils von Neuhoff, Brigitte Schlegelberger, Klaus Kuehlcke, Kevin D. Bunting, Sonja Schmidt, Annette Deichmann, Christof von Kalle, Boris Fehse, and Christopher Baum From the Department of Hematology, Hemostaseology and Oncology, and the Institute of Cellular and Molecular Pathology, Hannover Medical School, Germany; Bone Marrow Transplantation, University Hospital Eppendorf, Hamburg, Germany; University Hospital, Albert-Ludwig University, Freiburg, Germany; EUFETS AG, Idar-Oberstein, Germany; the Division of Hematology/Oncology and Center for Stem Cell and Regenerative Medicine, Case Western Reserve University, Cleveland, OH; and the Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, OH. Previous studies have demonstrated leukemic complications in mice after high-copy retroviral gene transfer of the multidrug resistance 1 (MDR1) cDNA, encoding a membrane-located efflux pump expressed in hematopoietic stem cells. In contrast, no such complications or MDR1-associated alterations of hematopoiesis were observed in numerous other studies exploring MDR1 gene transfer into cell lines, mice, dogs, nonhuman primates, and human subjects. Here, we show that leukemias associated with retroviral expression of MDR1 depend on high vector dose, and involve the selection of clones with combinatorial insertional mutagenesis of proto-oncogenes or other signaling genes. Compared with insertion patterns in normal long-term repopulating hematopoietic cells, such hits were overrepresented in leukemic clones, pointing to a causal role. A similar constellation of insertion sites was also observed in a leukemia arising after high-copy retroviral gene transfer of a fluorescent protein. Spectral karyotyping demonstrated additional chromosomal translocations in a subset of cases, indicative of secondary genetic instability. We also show that insertional mutants can be amplified in vitro prior to transplantation. On the basis of these findings, we suggest the use of preclinical dose-escalation studies to define a therapeutic index for retroviral transgene delivery. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y.-J. Kim, Y.-S. Kim, A. Larochelle, G. Renaud, T. G. Wolfsberg, R. Adler, R. E. Donahue, P. Hematti, B.-K. Hong, J. Roayaei, et al. Sustained high-level polyclonal hematopoietic marking and transgene expression 4 years after autologous transplantation of rhesus macaques with SIV lentiviral vector-transduced CD34+ cells Blood, May 28, 2009; 113(22): 5434 - 5443. [Abstract] [Full Text] [PDF] A. Ramezani, T. S. Hawley, and R. G. 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Li, M. H. Brugman, S. M. Chambers, C. A. Shaw, K. Pike-Overzet, D. d. Ridder, F. J. T. Staal, G. v. Keudell, et al. Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways Blood, March 1, 2007; 109(5): 1897 - 1907. [Abstract] [Full Text] [PDF] C. E. Dunbar The Yin and Yang of Stem Cell Gene Therapy: Insights into Hematopoiesis, Leukemogenesis, and Gene Therapy Safety Hematology, January 1, 2007; 2007(1): 460 - 465. [Abstract] [Full Text] [PDF] U. Modlich, J. Bohne, M. Schmidt, C. von Kalle, S. Knoss, A. Schambach, and C. Baum Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity Blood, October 15, 2006; 108(8): 2545 - 2553. [Abstract] [Full Text] [PDF] Y. Shou, Z. Ma, T. Lu, and B. P. Sorrentino Unique risk factors for insertional mutagenesis in a mouse model of XSCID gene therapy PNAS, August 1, 2006; 103(31): 11730 - 11735. [Abstract] [Full Text] [PDF] T. Neff, B. C. Beard, and H.-P. 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