Oligonucleotides induce apoptosis restricted to the t(14;18) DHL-4 cell line

Most human follicular B-cell lymphomas are associated with t(14;18) chromosome translocation that joins the bcl-2 gene with the IgH locus. This hybrid gene causes upregulation of BCL-2 protein expression, endowing cells with survival advantage. Although early BCL-2 overexpression is definitely responsible for immortalization/transformation, its exact role in the overt transformation as well as in the maintenance of the tumor phenotype is not known. The capacity of oligodeoxynucleotides (ODN) to modulate gene expression specifically has been exploited to downregulate the overexpression of BCL-2 protein in the SU-DHL-4 human follicular B-cell lymphoma line by the use of sense ODN or antisense ODN or antisense ODN designed to encompass the unique nucleotide sequence in the fusion region of the hybrid transcript. The specific downregulation of the bcl-2 transcript and of the relevant BCL-2 protein in the treated cells activated programed cell death and inhibited growing cells. The antitumor activity was restricted to the DHL-4 cell line carrying the specific nucleotide sequence at the bcl-2/IgH joining region. Thus, DHL-4 lymphoma cells derived from the acute phase of human follicular B-cell lymphoma, although endowed with additional activated oncogenes, were growth inhibited by bcl-2 downregulation with additional activated oncogenes, were growth inhibited by bcl-2 downregulation in a genetically restricted fashion. The biological activity was exerted exclusively by ODNs synthesized in the sense orientation. The sense ODNs have been proposed to anneal the hybrid bcl-2/IgH antisense RNA as identified in this study.