EFFECT OF INTERLEUKIN-1-BETA CONVERTING-ENZYME-INHIBITOR ON ACUTE MYELOGENOUS LEUKEMIA PROGENITOR PROLIFERATION

Interleukin-1 beta (IL-1 beta) converting enzyme (ICE) is a cysteine p rotease that specifically cleaves precursor IL-1 beta to its biologica lly active form. Recent studies have also implicated ICE in the induct ion of apoptosis in vertebrate cells. Because IL-1 plays a major role in acute myelogenous leukemia (AML) blast proliferation, we sought to investigate the effect of ICE inhibition on AML progenitors. To do thi s, we used bocaspartyl (benzyl) chloromethylketone (BACMK) an inhibito r designed to penetrate cells and bind covalently to the active site o f ICE. Our preliminary experiments showed that incubation of activated peripheral blood cells with 2.5 mu mol/L of BAMCK downregulated produ ction of mature IL-1 beta but had no effect on tumor necrosis factor-c t. To test the effects of the inhibitor on AML cells, we first used th e OCI/AML3 cell line. We found that these cells produce IL-1 beta and bind the biotinylated cytokine and that IL-1 inhibitors, such as IL-1 neutralizing antibodies, IL-1 receptor antagonist, and soluble IL-1 re ceptors, specifically inhibit OCI/AML3 proliferation, indicating that IL-1 beta is an autocrine growth factor for OCI/AML3 cells. The ICE in hibitor suppressed OCI/AML3 growth in a dose-dependent manner (at 0.4 to 4 mu mol/L) and downregulated mature IL-1 beta production, as asses sed by Western immunoblotting. Similar results were obtained with marr ow aspirates from 16 AML patients. The ICE inhibitor suppressed prolif eration of AML precursors (by up to 78%; mean, 44%) in a dose-dependen t fashion at concentrations ranging from 0.4 to 5 mu mol/L but not pro liferation of normal marrow progenitors; the suppressive effect was re versed by IL-1 beta. Furthermore, incubation of AML cells with 4 mu mo l/L BAMCK downregulated the production of mature IL-1 beta, suggesting that the growth-inhibitory effect is mediated through suppression of the biologically active cytokine. Our data indicate that inhibition of ICE suppresses AML blast proliferation and suggest that ICE inhibitor s may have a role in future therapies for AML. (C) 1995 by The America n Society of Hematology.