REGULATION OF CHEMORESISTANCE BY THE BCL-2 ONCOPROTEIN IN NON-HODGKINS-LYMPHOMA AND LYMPHOCYTIC-LEUKEMIA CELL-LINES

Background: The bcl-2 gene becomes activated by 14; 18 chromosomal translocations in the majority of low-grade non-Hodgkin's lymphomas (NHLs) and is expressed at high levels in the absence of gene rearrangements in a high proportion of B-cell chronic lymphocytic leukemias (B-CLLs). The protein encoded by bcl-2 contributes to neoplastic cell expansion by prolonging cell survival through its ability to block programmed cell death (apoptosis). Because many chemotherapeutic drugs have been shown ultimately to kill tumor cells through mechanisms consistent with programmed cell death, we tested whether the relative levels of bcl-2 oncoprotein influence the sensitivity of lymphoma and leukemia cell lines to killing by conventional cytotoxic drugs commonly used in the treatment of cancer. Methods: Leukemia cell lines with low levels of bcl-2 expression were stably infected with recombinant bcl-2 retroviruses to achieve elevations in bcl-2 protein levels. Lymphoma cell lines with high levels of bcl-2 expression as the result of 14; 18 translocations were either stably transfected with inducible bcl-2 antisense expression plasmids or treated with bcl-2 antisense oligonucleotides to achieve reductions in bcl-2 protein levels. The sensitivity of these genetically modified cells to killing by various antineoplastic drugs was then determined. Results: Gene transfer-mediated elevations in bcl-2 protein levels in lymphocytic leukemia cell lines was correlated with markedly elevated resistance to killing by all cytotoxic drugs tested. Conversely, antisense-mediated reductions in bcl-2 protein levels in t(14;18)-containing NHL cell lines resulted in enhanced sensitivity to all anticancer-drugs. Conclusions: The relative levels of bcl-2 oncoprotein represent one of the key determinants of the sensitivity of lymphocytic cells to killing by essentially all drugs currently available for the treatment of cancer.