Down-regulation of retroviral transgene expression during differentiation of progenitor-derived dendritic cells.

Abstract:

OBJECTIVE:Hematopoietic progenitor cells are a promising source for generation of genetically modified dendritic cells. A prerequisite for using these cells in therapeutic approaches is stable vector-mediated transgene expression during and after cell maturation. We investigated the expression of enhanced green fluorescence protein (EGFP) mediated by retroviral vectors in dendritic cells and other hematopoietic cells differentiated in vitro. MATERIAL AND METHODS:CD34(+) cells were efficiently transduced with retroviral vector constructs known to mediate different expression levels due to distinct cis-acting elements. EGFP(+) cells were purified by cell sorting and differentiated to monocytes, granulocytes, dendritic cells, and erythrocytes. Coexpression of EGFP and cell type-specific markers was analyzed by flow cytometry. RESULTS:Transgene expression from various retroviral vectors was silenced exclusively in dendritic cells, but not in other mature myeloid cells. Loss of EGFP was most pronounced in cells initially displaying low expression levels. This was confirmed by using a retroviral vector coding for a variant of EGFP with significantly reduced half-life. In contrast, a majority of dendritic cells showed stable expression when a self-inactivating retroviral construct using an internal cytomegalovirus promotor was used. CONCLUSIONS:We suggest that expression from the retroviral long terminal repeat is silenced during dendritic cell differentiation in vitro. High levels of stable transgene product in progenitor cells may mask a loss of expression. An improvement of retroviral vectors mediating stable transgenic expression is necessary for therapeutic approaches using gene-modified dendritic cells.

journal_name

Exp Hematol

journal_title

Experimental hematology

authors

Lindemann C,Schilz AJ,Emons B,Baum C,Löw R,Fauser AA,Kuehlcke K,Eckert HG

doi

10.1016/s0301-472x(01)00778-0

keywords:

subject

Has Abstract

pub_date

2002-02-01 00:00:00

pages

150-7

issue

2

eissn

0301-472X

issn

1873-2399

pii

S0301472X01007780

journal_volume

30

pub_type

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