ROLE OF INTERLEUKIN-1-BETA CONVERTING-ENZYME (ICE) IN LEUKEMIA

Interleukin (IL)-1 is a proinflammatory cytokine that plays a pivotal role in driving the in vitro proliferation of leukemic cells through a utocrine or paracrine pathways. Both IL-l genes, IL-1 alpha and the pr ominent IL-1 beta, produce 31 kDa proteins. Whereas the precursor (pro ) 31 kDa form of IL-1 alpha is biologically active, pro-IL-1 beta is i nactive unless cleaved to its mature form by a cytoplasmic cysteine pr otease termed IL-1 beta converting enzyme (ICE). Although ICE was firs t thought to be a unique enzyme with a single biologic activity, sever al investigators have demonstrated that ICE shares sequence homology w ith the protein product of ced-3, the gene for cell death of the nemat ode Caenorhabditis elegans, and can induce apoptosis in different cell ular systems. However, recent data indicate that ICE is a member of an increasingly recognized family of ICE-related molecules whose other m embers, such as CPP32, do not cleave pro-IL-1 beta but rather are effe ctive inducers of apoptotic cell death. We recently investigated the e ffect of ICE inhibition on acute myelogenous leukemia (AML) colony gro wth. We found that inhibition of ICE reduced the production of mature IL-1 beta and suppressed the proliferation of AML colony-forming units , confirming the central role of IL-1 beta in AML progenitor prolifera tion. These data suggest that the primary role of ICE in AML cells is cleavage of pro-IL-1 beta rather than induction of apoptosis and that the antileukemic activity of specific ICE inhibitors warrants further exploitation.