NOVEL RETROVIRAL VECTORS FOR EFFICIENT EXPRESSION OF THE MULTIDRUG-RESISTANCE (MDR-1) GENE IN EARLY HEMATOPOIETIC-CELLS

被引:201
|
作者
BAUM, C
HEGEWISCHBECKER, S
ECKERT, HG
STOCKING, C
OSTERTAG, W
机构
[1] UNIV HAMBURG, HEINRICH PETTE INST EXPTL VIROL & IMMUNOL, ZELL & VIRUSGENET ABT, D-20251 HAMBURG, GERMANY
[2] UNIV HAMBURG, MED KLIN, ONKOL & HAMATOL ABT, D-20251 HAMBURG, GERMANY
关键词
D O I
10.1128/JVI.69.12.7541-7547.1995
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
We present data that retroviral gene expression in early hematopoietic cells is subjected to transcriptional controls similar to those previously described for embryonic stem cells. Transient transfection experiments revealed that both the viral enhancer region in the U3 region of the long terminal repeat as well as a repressor element coincident,vith the primer binding site of Moloney leukemia viruses are limiting for expression in hematopoietic cells in a differentiation-dependent manner. Within the group of Moloney leukemia virus-related viruses, only the myeloproliferative sarcoma virus showed high enhancer activity in myeloid (including erythroid) cells, In contrast, enhancer regions related to the Friend mink cell focus-forming viruses mediate much higher gene expression levels in both multipotent and lineage-committed myeloid cells, In addition, transcriptional repression related to sequences in the primer binding site of Moloney leukemia virus-derived vectors is also found in early hematopoietic cells and can be overcome by using the corresponding sequences of the murine embryonic stem cell virus. On the basis of these results, two types of novel retroviral hybrid vectors were developed; they combine the U3 regions of either the Friend mink cell focus-forming virus family or the myeloproliferative sarcoma virus with the primer binding site of the murine embryonic stem cell virus. When used to express the human multiple drug resistance gene, these vectors substantially improve protection to cytostatic drugs in transduced hematopoietic cell lines FDC-Pmix, TF-1, and K-562 in comparison with Moloney leukemia virus-derived vectors presently used for the stem cell protection approach in somatic gene therapy.
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页码:7541 / 7547
页数:7
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