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Oligonucleotide uptake in human hematopoietic cells is increased in leukemia and is related to cellular activation
Q Zhao1, X Song, T Waldschmidt
1Veterans Affairs Medical Center, Iowa City, USA.
Abstract:
The use of antisense oligonucleotides as tools for modulating gene expression represents a novel strategy for designing drugs to treat a variety of diseases. Several factors, including cellular uptake and internalization of the oligonucleotides, are important parameters in determining the effectiveness of antisense agents such as therapeutic drugs. We have studied oligonucleotides uptake in normal and leukemic human hematopoietic cells, such as peripheral blood, bone marrow (BM), and HL-60 cell line; and have found that, in normal human blood and BM, myeloid cells and B cells preferably took up more oligonucleotides than T cells. There was no marked difference in oligonucleotide uptake between CD4+ helper T cells and CD8+ cytolytic T cells. Leukemic cells had greater oligonucleotide uptake than their normal counterparts. Furthermore, oligonucleotide uptake was closely related to cell activation status and can be modulated by growth factors or inhibitors. These studies provide a basis for using oligonucleotides as therapeutic drugs both in vitro and in vivo.
Insights
Antisense oligonucleotides show promise as therapeutic drugs. Leukemic cells and certain normal blood cells exhibit higher uptake, suggesting targeted delivery potential for gene expression modulation.
Area of Science:
- Biotechnology
- Molecular Biology
- Pharmacology
Background:
- Antisense oligonucleotides (ASOs) are emerging as a novel therapeutic strategy for gene expression modulation.
- Cellular uptake and internalization are critical for the efficacy of ASO-based drugs.
- Understanding ASO uptake in different cell types is essential for optimizing therapeutic applications.
Purpose of the Study:
- To investigate the cellular uptake of oligonucleotides in normal and leukemic human hematopoietic cells.
- To identify factors influencing oligonucleotide uptake, such as cell type and activation status.
Main Methods:
- Studied oligonucleotide uptake in normal human peripheral blood, bone marrow (BM), and HL-60 leukemic cell line.
- Compared uptake across different hematopoietic cell subsets (myeloid, B cells, T cells, CD4+, CD8+).
- Assessed the impact of cell activation status, growth factors, and inhibitors on oligonucleotide uptake.
Main Results:
- Normal myeloid and B cells demonstrated higher oligonucleotide uptake compared to T cells.
- No significant difference in uptake was observed between CD4+ and CD8+ T cells.
- Leukemic cells exhibited greater oligonucleotide uptake than their normal counterparts.
- Oligonucleotide uptake correlated with cell activation status and was modifiable by growth factors and inhibitors.
Conclusions:
- Hematopoietic cell type and activation status significantly influence oligonucleotide uptake.
- Leukemic cells show enhanced uptake, suggesting potential for targeted therapy.
- Findings support the development of oligonucleotide-based therapeutics for various diseases, with potential for in vitro and in vivo applications.