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Blood, 15 December 2001, Vol. 98, No. 13, pp. 3607-3617
GENE THERAPY
Effects of CD2 locus control region sequences on gene expression
by retroviral and lentiviral vectors
Stefano Indraccolo,
Sonia Minuzzo,
Francesca Roccaforte,
Rita Zamarchi,
Walter Habeler,
Laura Stievano,
Valeria Tosello,
Dieter Klein,
Walter H. Günzburg,
Giuseppe Basso,
Luigi Chieco-Bianchi, and
Alberto Amadori
From the IST-Viral and Molecular Oncology
Section, the Department of Oncology and Surgical Sciences, and the
Department of Pediatrics, University of Padua, Italy; and the Institute
of Virology, University of Veterinary Sciences, Vienna, Austria.
Locus control region (LCR) sequences are involved in the
establishment of open chromosomal domains. To evaluate the possibility of exploiting the human CD2 LCR to regulate gene expression by Moloney
murine leukemia virus (Mo-MLV)-based retroviral vectors in T cells, it
was included in vectors carrying the enhanced green fluorescence
protein (EGFP) reporter gene; then transduction in vitro of lymphoid
and nonlymphoid cell lines was performed. Deletion of the viral
enhancer in the Mo-MLV long terminal repeat was necessary to detect LCR
activity in the context of these retroviral vectors. It was found that
a full-length (2.1 kb), but not a truncated (1.0 kb), CD2 LCR retained
the ability to modulate reporter gene expression by Mo-MLV-derived
retroviral vectors, leading to a homogeneous, unimodal pattern of EGFP
expression that remained unmodified in culture over time, specifically
in T-cell lines; on the other hand, viral titer was strongly reduced
compared with vectors not carrying the LCR. Lentiviral vectors
containing the CD2 LCR could be generated at higher titers and were
used to analyze its effects on gene expression in primary T cells.
Subcutaneous implantation of genetically modified cells in
immunodeficient mice showed that retroviral vectors carrying the CD2
LCR conferred an advantage in terms of transgene expression in vivo,
compared with the parental vector, by preventing the down-modulation of EGFP expression. These findings suggest a potential application of this
LCR to increase gene expression by retroviral and lentiviral vectors in
T lymphocytes.
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