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Chronic Lymphocytic Leukemia, Normal B and T Cells

Thymidine-phosphorothioate oligonucleotides induce activation and apoptosis of CLL cells independently of CpG motifs or BCL-2 gene interference

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Abstract

We compared antisense phosphorothioate oligonucleotides (PS-ODN) that target BCL-2 such as Genasense® (G3139-PS), with other PS-ODN or phosphodiester-ODN (PO-ODN) in their relative capacity to induce apoptosis of chronic lymphocytic leukemia (CLL) B cells in vitro. Surprisingly, we found that thymidine-containing PS-ODN, but not PO-ODN, induced activation and apoptosis of CLL cells independent of BCL-2 antisense sequence or CpG motifs. All tested thimidine-containing PS-ODN, irrespective of their primary sequences, reduced the expression of Bcl-2 protein and increased the levels of the proapoptotic molecules p53, Bid, Bax in CLL cells. Apoptosis induced by thymidine-containing PS-ODN was preceded by cellular activation, could be blocked by the tyrosine-kinase inhibitor imatinib mesylate (Gleevec®), and was dependent on ABL kinase. We conclude that thymidine-containing PS-ODN can activate CLL cells and induce apoptosis via a mechanism that is independent of BCL-2 gene interference or CpG motifs.

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Acknowledgements

This work was supported by a National Institutes of Health K08 Grant CA106 605-01 (JEC) and PO1 Grant CA 81534 for the CLL Research Consortium (TJK). The authors acknowledge the helpful technical support provided by Dr Anissa Agadir from Pharmingen, La Jolla, CA and Dr Laura Rassenti from the Chronic lymphocytic leukemia Research Consortium (C.R.C)

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  1. M Motta

    Present address: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA

Authors and Affiliations

  1. John and Rebecca Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

    J E Castro, C E Prada, R A Aguillon, T Fukuda, M Motta, C Wu, F Dicker, D A Carson & T J Kipps

  2. The Burnham Institute, La Jolla, CA, USA

    S Kitada & J C Reed

  3. Department of Biology, University of California San Diego, La Jolla, CA, USA

    G Sun & J Y J Wang

  4. Chronic lymphocytic leukemia Research Consortium (C.R.C), La Jolla, CA, USA

    J E Castro, C E Prada, R A Aguillon, S Kitada, T Fukuda, C Wu, F Dicker, D A Carson, J C Reed & T J Kipps

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Castro, J., Prada, C., Aguillon, R. et al. Thymidine-phosphorothioate oligonucleotides induce activation and apoptosis of CLL cells independently of CpG motifs or BCL-2 gene interference. Leukemia 20, 680–688 (2006). https://doi.org/10.1038/sj.leu.2404144

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