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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-02-0627.
Submitted February 27, 2002
Accepted October 29, 2002
Retroviral vector integration occurs into preferred genomic targets of human bone marrow repopulating cells
Stephanie Laufs, Bernhard Gentner, K Zsuzsanna Nagy, Anna Jauch, Axel Benner, Sonja Naundorf, Klaus Kuehlcke, Bernhard Schiedlmeier, Anthony D Ho, W Jens Zeller, and Stefan Fruehauf*
Research Program Diagnostic and Experimental Therapy, German Cancer Research Center, Heidelberg, Germany
Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
Research Program Biostatistics and Epidemiology, German Cancer Research Center, Heidelberg, Germany
EUFETS AG, Idar-Oberstein, Germany
Experimental Cell Therapy, Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany
Department of Internal Med. V, University of Heidelberg, Heidelberg, Germany
* Corresponding author; email: stefan_fruehauf{at}med.uni-heidelberg.de.
Increasing use of hematopoietic stem cells for retroviral vector-mediated gene therapy and recent reports on insertional mutagenesis in mice and humans has created intense interest to characterize vector integrations on a genomic level. We studied retrovirally transduced human peripheral blood progenitor cells with bone marrow repopulating ability in immune-deficient mice. Using a highly sensitive and specific ligation-mediated PCR followed by sequencing of vector integration sites, we found a multitude of simultaneously active human stem cell clones eight weeks after transplantation. Vector integrations occurred with significantly increased frequency into chromosomes 17 and 19 and into specific regions of chromosomes 6, 13 and 16 although the majority of chromosomes were targeted. Preferred genomic target sites have previously only been reported for wild-type retroviruses. Our findings reveal for the first time that retroviral vector integration into human marrow-repopulating cells can be nonrandom (P = 0.00037).
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