THE ANTISENSE BCL-2-IGH TRANSCRIPT IS AN OPTIMAL TARGET FOR SYNTHETICOLIGONUCLEOTIDES

In most human follicular B cell lymphomas the bcl-2 gene is up-regulat ed 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)-positi ve cells a bcl-2-IgH mRNA in the antisense orientation, putatively res ponsible for the overexpression of bcl-2, Herein we show that this chi meric antisense transcript is an optimal target For synthetic oligodeo xynucleotides (ODNs), A variety of sense-oriented oligonucleotides hav e been designed that target the antisense transcript in regions endowe d with a sequence specificity presumably restricted to an individual c ell line (the bcl-2-IgH fusion regions) or extended to all t(14;18) ce lls (the ectopic bcl-2 segment upstream from the major breakpoint regi on 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 ta rgeting the fusion region was restricted to each individual cell line, whereas the activity of all ODNs targeting the common bcl-2 and IgH s egments was extended to all t(14;18) cell lines tested, These sense OD Ns were not effective in untranslocated cell lines, Antisense-oriented ODNs, complementary to the bcl-2-IgH mRNA, and control ODNs (scramble d, inverted, or mismatched) were biologically ineffective, The selecti vity and efficacy of all sense ODNs tested provide support for the dev elopment of therapeutic ODNs targeting the bcl-2-IgH antisense transcr ipt expressed in human follicular lymphomas.