A BCL-2 IGH ANTISENSE TRANSCRIPT DEREGULATES BCL-2 GENE-EXPRESSION INHUMAN FOLLICULAR LYMPHOMA T(14-18) CELL-LINES/

The 14;18 chromosome translocation, characteristic of most human folli cular B-cell lymphomas, juxtaposes the bcl-2 gene with the IgH locus, creating a bcl-2/IgH hybrid gene, By mechanisms that are still under i nvestigation, this event increases the cellular levels of the bcl-2 mR NA and thereby induces an overproduction of the antiapoptotic BCL-2 pr otein which is likely responsible for neoplastic transformation, In an effort to identify potential upregulators of bcl-2 activity in t(14;1 8) cells, we found, by strand-specific RT-PCR, a bcl-2 antisense trans cript that is present in the t(14;18) DOHHZ and SU-DHL-4 but not in th e t(14;18)-negative Raji and Jurkat lymphoid cell lines, and thus appe ars to be dependent on the bcl-2/IgH fusion, This antisense transcript is a hybrid bcl-2/IgH RNA, that originates in the IgH locus, encompas ses the t(14;18) fusion site and spans at least the complete 3' UTR re gion of the bcl-2 mRNA, To achieve some insight into its biological fu nction, we treated the t(14;18) DOHH2 cell line with oligonucleotides (ODNs) by specifically targeting the bcl-2/IgH antisense strand, These ODNs lowered bcl-2 gene expression, inhibited neoplastic cell growth by inducing apoptosis, We would like to propose the hypothesis that th e bcl-2/IgH antisense transcript may contribute, by an unknown mechani sm, to upregulation of bcl-2 gene expression in t(14;18) cells. The po ssibility has been considered that the hybrid antisense transcript mas k AU-rich motifs present in the 3' UTR of the bcl-2 mRNA characterized in other genes as mRNA destabilizing elements.