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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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Submitted August 28, 2006
Accepted October 18, 2006
Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways
Olga S. Kustikova, Hartmut Geiger, Zhixiong Li, Martijn H. Brugman, Stuart M. Chambers, Chad A. Shaw, Karin Pike-Overzet, Dick de Ridder, Frank J.T. Staal, Gottfried von Keudell, Kerstin Cornils, Kalpana J. Nattamai, Ute Modlich, Gerard Wagemaker, Margaret A. Goodell, Boris Fehse, and Christopher Baum*
Dept of Experimental Hematology, Hannover Medical School, Hannover, Germany
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Dept of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
Center for Cell and Gene Therapy, Cell & Molecular Biology Program, Baylor College of Medicine, Houston, TX, United States
Dept of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, United States
Dept of Immunology, Erasmus Medical Center, Rotterdam, Netherlands
Delft University of Technology, Delft, Netherlands
Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
* Corresponding author; email: baum.christopher{at}mh-hannover.de.
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 non-malignant cells is a particularly interesting phenotype as it may be caused by the dysregulation of genes that impact on self-renewal and competitive fitness. We have accumulated 280 retrovirus vector insertion sites (RVIS) from murine long-term studies resulting in benign or malignant clonal dominance. 22.5% of the RVIS are located in or near (up to 100 kb) 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). RVIS 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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