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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.
Submitted August 28, 2006
Dept of Experimental Hematology, Hannover Medical School, Hannover, 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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