The antisense bcl-2-IgH transcript is an optimal target for synthetic oligonucleotides

Susanna Morelli, Domenico Delia, Sergio Capaccioli, Alessandro Quattrone, Nicola Schiavone, Anna Bevilacqua, Silvia Tomasini, Angelo Nicolin

Research output: Contribution to journalArticle

Abstract

In most human follicular B cell lymphomas the bcl-2 gene is up-regulated as a result of the t (14;18) chromosomal translocation generating a hybrid bcl-2-IgH mRNA. Recently, we have identified in t(14;18)-positive cells a bcl-2-IgH mRNA in the antisense orientation, putatively responsible for the overexpression of bcl-2. Herein we show that this chimeric antisense transcript is an optimal target for synthetic oligodeoxynucleotides (ODNs). A variety of sense-oriented oligonucleotides have been designed that target the antisense transcript in regions endowed with a sequence specificity presumably restricted to an individual cell line (the bcl-2-IgH fusion regions) or extended to all t(14;18) cells (the ectopic bcl-2 segment upstream from the major breakpoint region and the IgH segment). All sense- oriented ODNs complementary to the antisense transcript induced an early strong inhibition of cell growth and a late fulminant cell death. As expected, the activity of ODNs targeting the fusion region was restricted to each individual cell line, whereas the activity of all ODNs targeting the common bcl.2 and IgH segments was extended to all t(14;18) cell lines tested. These sense ODNs were not effective in untranslocated cell lines. Antisense- oriented ODNs, complementary to the bcl-2-IgH mRNA, and control ODNs (scrambled, inverted, or mismatched) were biologically ineffective. The selectivity and efficacy of all sense ODNs tested provide support for the development of therapeutic ODNs targeting the bcl-2-IgH antisense transcript expressed in human follicular lymphomas.

Original languageEnglish
Pages (from-to)8150-8155
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number15
DOIs
Publication statusPublished - Jul 22 1997

Keywords

  • Antisense RNA
  • Antitumor
  • Apoptosis
  • bcl-2 regulation
  • Hybrid RNA

ASJC Scopus subject areas

  • Genetics
  • General

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    Morelli, S., Delia, D., Capaccioli, S., Quattrone, A., Schiavone, N., Bevilacqua, A., Tomasini, S., & Nicolin, A. (1997). The antisense bcl-2-IgH transcript is an optimal target for synthetic oligonucleotides. Proceedings of the National Academy of Sciences of the United States of America, 94(15), 8150-8155. https://doi.org/10.1073/pnas.94.15.8150