Induction of apoptosis in myeloid leukaemic cells by ribozymes targeted against AML1/MTG8

The translocation (8;21)(q22;q22) is a karyotypic abnormality detected in a cute myeloid leukaemia (AML) M2 and results in the formation of the chimeri c fusion gene AML1/MTG8. We previously reported that two hammerhead ribozym es against AML1/MTG8 cleave this fusion transcript and also inhibit the pro liferation of myeloid leukaemia cell line Kasumi-1 which possesses t(8;21)( q22;q22). In this study, we investigated the mechanisms of inhibition of pr oliferation in myeloid leukaemic cells with t(8;21)(q22;q22) by ribozymes. These ribozymes specifically inhibited the growth of Kasumi-1 cells, but di d not affect the leukaemic cells without t(8;21)(q22;q22). We observed the morphological changes including chromatin condensation, fragmentation and t he formation of apoptotic bodies in Kasumi-1 cells incubated with ribozymes for 7 days. In addition, DNA ladder formation was also detected after incu bation with ribozymes which suggested the induction of apoptosis in Kasumi- 1 cells by the AML1/MTG8 ribozymes. However, the ribozymes did not induce t he expression of CD11b and CD14 antigens in Kasumi-1 cells. The above data suggest that these ribozymes therefore inhibit the growth of myeloid leukae mic cells with t(8;21)(q22;q22) by the induction of apoptosis, but not diff erentiation. We conclude therefore that the ribozymes targeted against AML1 /MTG8 may have therapeutic potential for patients with AML carrying t(8;21) (q22;q22) while, in addition, the product of the chimeric gene is responsib le for the pathogenesis of myeloid leukaemia.