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 Blood, 1 March 2007, Vol. 109, No. 5, pp. 1897-1907.
Prepublished online as a Blood First Edition Paper on November 21, 2006; DOI 10.1182/blood-2006-08-044156.

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HEMATOPOIESIS

Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways

Olga S. Kustikova1,2, Hartmut Geiger3, Zhixiong Li1, Martijn H. Brugman4, Stuart M. Chambers5, Chad A. Shaw6, Karin Pike-Overzet7, Dick de Ridder8, Frank J. T. Staal7, Gottfried von Keudell2, Kerstin Cornils2, Kalpana Jekumar Nattamai3, Ute Modlich1, Gerard Wagemaker4, Margaret A. Goodell5,6, Boris Fehse2, and Christopher Baum1,3

1 Department of Experimental Hematology, Hannover Medical School, Germany; 2 Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 3 Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, OH; 4 Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands; 5 Center for Cell and Gene Therapy and Cell and Molecular Biology Program, Baylor College of Medicine, Houston, TX; 6 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 7 Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands; 8 Information and Communication Theory Group, Faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, The Netherlands

Evidence from model organisms and clinical trials reveals that the random insertion of retrovirus-based vectors in the genome of long-term repopulating hematopoietic cells may increase self-renewal or initiate malignant transformation. Clonal dominance of nonmalignant cells is a particularly interesting phenotype as it may be caused by the dysregulation of genes that affect self-renewal and competitive fitness. We have accumulated 280 retrovirus vector insertion sites (RVISs) from murine long-term studies resulting in benign or malignant clonal dominance. RVISs (22.5%) are located in or near (up to 100 kb [kilobase]) to known proto-oncogenes, 49.6% in signaling genes, and 27.9% in other or unknown genes. The resulting insertional dominance database (IDDb) shows substantial overlaps with the transcriptome of hematopoietic stem/progenitor cells and the retrovirus-tagged cancer gene database (RTCGD). RVISs preferentially marked genes with high expression in hematopoietic stem/progenitor cells, and Gene Ontology revealed an overrepresentation of genes associated with cell-cycle control, apoptosis signaling, and transcriptional regulation, including major "stemness" pathways. The IDDb forms a powerful resource for the identification of genes that stimulate or transform hematopoietic stem/progenitor cells and is an important reference for vector biosafety studies in human gene therapy.


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C. Cattoglio, G. Facchini, D. Sartori, A. Antonelli, A. Miccio, B. Cassani, M. Schmidt, C. von Kalle, S. Howe, A. J. Thrasher, et al.
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