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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-02-0627.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2191-2198
GENE THERAPY
Retroviral vector integration occurs in 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
From the German Cancer Research Center, Research
Program Diagnostics and Experimental Therapy, and Research
Program Biostatistics and Epidemiology, Heidelberg,
Germany; Institute of Human Genetics and Department of
Internal Medicine V, University of Heidelberg, Heidelberg,
Germany; Europäisches Institut für Forschung
und Entwicklung von Transplantationsstrategien (EUFETS)
AG, Idar-Oberstein, Germany; Experimental Cell
Therapy, Department of Hematology and Oncology, Hannover Medical
School, Hannover, Germany.
Increasing use of hematopoietic stem cells for retroviral
vector-mediated gene therapy and recent reports on insertional
mutagenesis in mice and humans have 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. By using a
highly sensitive and specific ligation-mediated polymerase chain
reaction (PCR) followed by sequencing of vector integration
sites, we found a multitude of simultaneously active human stem cell
clones 8 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 most of the
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 = .000 37).
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