Modulation of acute myeloblastic leukemia (AML) cell proliferation and blast colony formation by antisense oligomer for IL-1 beta converting enzyme (ICE) and IL-1 receptor antagonist (IL-1ra).

In the present study we investigated the effects of IL-1 antagonism on the autonomous growth of cells in acute myeloblastic leukemia (AML). To examine the role of pro-IL-1 processing, antisense technology was employed with 16-mer phosphorothioate oligodeoxynucleotide directed against human IL-1 beta converting enzyme (ICR) in 7 randomly selected AML cases. The addition of 10-75 mu M of antisense oligonucleotide (but not of control oligonucleotide) significantly inhibited spontaneous proliferation of bone marrow- (BM) and peripheral blood- (PB) derived low density leukemic cells in a dose-dependent way. Similarly, spontaneous as well as induced CFU-AML colony formation was inhibited by human ICE antisense oligonucleotide with sample-to-sample variability. In separate experiments, in order to examine the effects of blockade of endogenously produced IL-1 to IL-1 receptors, the functional activity of human recombinant IL-1 receptor antagonist (IL-1ra) was tested. Continuous exposure to high concentrations of IL-1ra (up to 100 mu g/ml) produced dose-dependent inhibition of spontaneous proliferatioin of the BM-derived blast cells from 9 of the 14 patients and of the PB-derived cells from 10 of the 14 patients. However, in some of these patients, the lower IL-1ra doses (down to 100 ng/ml) induced potentiation of spontaneous proliferation, suggesting a novel regulatory pathway for IL-1 receptor engagement. Similar results were obtained on CFU-AML colony formation, showing inhibition at higher IL-1ra doses, but in a few AML cases stimulatory effect at lower IL-1ra doses. Since the growth of AML cells, as presented here by spontaneous proliferation and AML progenitors, could be inhibited more efficiently by antisense oligonucleotide to ICE in comparison to IL-1ra, these experiments provide evidence that pro-IL-1 processing mediated by ICE is an essential step in the autonomous growth of AML cells.