Efficient adenovirus-mediated gene expression in malignant human plasma cells: relative lymphoid cell resistance.
Although adenoviruses offer several potential advantages as gene transfer vectors, some hematopoietic cells, particularly lymphoid cells, are considered relatively resistant to adenovirus-mediated gene transfer. To examine the role of adenovirus-mediated gene transfer in the lymphoid malignancy multiple myeloma (MM), we used E1- and E3-deleted adenoviral vectors to infect myeloma and lymphoma cell lines and subsequently primary bone marrow plasma cells and lymphocytes from patients with MM. Adenoviral vectors expressing LacZ or luciferase (AdCA18) reporter genes were used initially. Subsequently, we studied adenoviral vectors expressing genes of potential value in therapeutic immunomodulation, i.e., CD80 (AdB7-1) and interleukin-2 (AdIL-2). A human plasma cell line (OCI-My5) infected with LacZ or AdB7-1 vectors expressed the corresponding gene product in 95% and 85% of exposed cells, respectively. Time course experiments indicated that maximum expression of adenoviral transgenes in plasma cells was reached 3 days after infection. IL-2 was detected in the supernatant of AdIL-2-infected plasma cells, was functional, and could be detected for at least 30 days after infection. In contrast, three lymphoma cell lines (OCI-Ly2, OCI-Ly13.2, and OCI-Ly17) were significantly less sensitive to adenovirus infection, with relatively low efficiencies of gene transfer even using high adenoviral titers: Surface CD80 expression (13-25% of infected cells) and positive LacZ staining (0-5% of infected cells). Indeed, expression of luciferase was 96-168 times higher in AdCA18-infected OCI-My5 cells than in the OCI-Ly2 lymphoma cell line. Similar patterns were observed in primary plasma cells and lymphocytes from 19 MM patient bone marrow samples. After infection with AdB7-1, increased levels of CD80 expression on CD38 bright bone marrow plasma cells were observed in 84% of patients, with a 33% average increase in the number of plasma cells expressing CD80. In contrast, although increased CD80 expression was also detected on AdB7-1-infected CD19+ B lymphocytes from 63% of the MM patients, an average of only 14% of the infected lymphocytes demonstrated increased expression of CD80. Circulating T lymphocytes could not be transduced with AdB7-1. The relative resistance of B and T lymphocytes to adenovirus-mediated gene transfer warrants further investigation. Adenoviral vectors can efficiently infect malignant plasma cells and may be useful vehicles for therapeutic gene transfer.
Prince
H M
HM
The Toronto Hospital Oncology Gene Therapy Program, Department of Medicine and Mt. Sinai Hospital, Ontario, Canada.
Dessureault
S
S
Gallinger
S
S
Krajden
M
M
Sutherland
D R
DR
Addison
C
C
Zhang
Y
Y
Graham
F L
FL
Stewart
A K
AK
D000256:Adenoviridae; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D007763:Lac Operon / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D010950:Plasma Cells / Q000473:pathology*; D014407:Tumor Cells, Cultured
D008156:Luciferases