Inhibition of bcl-2 with antisense oligonucleotides induces apoptosis and increases the sensitivity of AML blasts to Ara-C.
We have previously shown that blasts from acute myeloid leukaemia (AML) patients which grow autonomously in culture have high bcl-2 expression which in turn has been linked to a poor clinical response to chemotherapy. The bcl-2 protein promotes cell survival by preventing the onset of apoptosis or programmed cell death following growth-factor deprivation. Bcl-2 has also been shown to be responsible for chemo-resistance in human leukaemic cell lines. Here we have investigated the role of bcl-2 expression in mediating resistance to apoptosis induced by cytosine arabinoside in vitro. The blasts from 17 AML patients exhibiting autonomous growth in a blast cell colony assay and expressing high levels of bcl-2 protein were studied. Incubation of the blasts with antisense oligonucleotides directed against bcl-2 mRNA resulted in a significant decrease in expression of the bcl-2 protein in seven of the 17 samples. In these seven cases the decreased expression of bcl-2 was accompanied by increased apoptosis and the susceptibility of the blasts to apoptosis induced by Ara-C was increased in the presence of bcl-2 antisense. As a high level of bcl-2 defines a group of AML patients who exhibit a poor response to chemotherapy, the demonstration that chemosensitivity of a significant proportion of these patients can be increased by bcl-2 antisense suggests this approach may have clinical potential.
Department of Haematology, Nottingham City Hospital, UK.
F J
FJ
Keith
D A
DA
Bradbury
Y M
YM
Zhu
N H
NH
Russell
D017209:Apoptosis; D001483:Base Sequence; D003561:Cytarabine / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured
D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D003561:Cytarabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor