Apoptosis 2004; 9: 705–715 C  2004 Kluwer Academic Publishers The inhibitor of apoptosis protein family and its antagonists in acute leukemias A. Wrzesie ´ n-Ku´ s, P. Smolewski, A. Sobczak-Pluta, A. Wierzbowska and T. Robak Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, Pabianicka 62, 93-513 Lodz, Poland The Inhibitor of Apoptosis Protein family (IAP) functions as inhibitors of apoptotic pathways, both death receptor- and mitochondrial mediated. We detail the current body of knowledge for the IAP family with regard to their structure and function, their expression in normal and leukemic cells, and their prognostic importance in acute leukemia. Although there is some evidence that IAPs play an impor- tant role in the chemoresistance of leukemia cell lines, little is known about their influence on this phenomenon in acute leukemia cells of human origin. IAPs are also explored as a specific target for new antitumor strate- gies, including antisense oligonucleotides of XIAP (X- chromosome-linked IAP) or survivin and small molecules of polyphenylurea-based XIAP inhibitors. Several proteins negatively regulate the function of the IAP family. One of those antagonists is Smac/DIABLO. Short peptides of Smac were found to enhanced apop- tosis, induced by chemo- or immunotherapy, in the leukemic cells in vitro. Moreover, small-molecule agents, resembling Smac/DIABLO in function, were shown to po- tentiate cytotoxicity of chemotherapy in different malig- nancies. IAPs, exhibiting downstream influence on both exter- nal and intrinsic pathways as well as on some caspase- independent mechanisms of apoptosis, are potentially at- tractive target for anti-tumor therapy, although their role in the pathology and prognosis of acute leukemia has to be further elucidated. Keywords: acute leukemia; antagonists of IAP family; apop- tosis; IAP. Introduction The impaired balance between cell proliferation and their proclivity to undergo apoptosis may be crucial for the development of various malignant hematological disorders. 1,2 Several abnormalities in apoptosis regulatory mechanisms leading to resistance to caspase-dependent cell death were reported in tumor cells from patients with acute leukemias. A number of studies indicate, that Correspondence to: Prof. Tadeusz Robak, MD, PhD, Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, Pabianicka 62, 93-513 Lodz, Poland. Tel.: (42)6895191; Fax: (42)6895192; e-mail: robaktad@csk.am.lodz.pl in these cells the complex of caspases-dependent ma- chinery is conserved, however, the expression of partic- ular proteolytic enzymes, adaptor molecules and pro- or anti-apoptotic regulatory proteins vary depend on type of leukemia and individuals. These differences can be poten- tially important for predicting of response to treatment. Resistance to apoptosis is primary cause of treatment fail- ure in acute leukemia. 3 The critical event of apoptosis is activation of caspases (c ysteine-aspartic acid specific pro- teases) via death receptor (external) and mitochondrial (intrinsic) pathways, what initiate DNA fragmentation, cleavage of several critical proteins and, finally, cell dis- integration. Moreover, caspase-independent mode of cell death as triggered by mitochondrial apoptosis inducing factor (AIF) has been also found. 4–6 The process of apoptosis is regulated on multiple levels by several regulatory mechanisms. Inhibitor of apoptosis protein family (IAP) functions as inhibitors of caspase- dependent cell death. 7,8 Overexpression of IAPs had been found in a wide variety of cancer cell lines and primary tu- mor biopsy samples, including leukemic cell lines or blasts isolated from patients with acute leukemia. 9–11 The po- tential role of the IAPs for defective apoptotis regulatory mechanisms and leukemic clone progression or develop- ment of chemoresistance is currently under evaluation. Several proteins have been found to negatively regu- late the function of the IAPs, such as Smac/DIABLO (a second mitochondrial derived activator of caspase/direct IAP binding protein with low pI), HtrA2/Omi (high tem- perature requirement A) and XIAP-associated factor 1 (XAF1). However, their expression and function in neo- plastic cells is less known. In this paper we review the current knowledge con- cerning the expression and potential role of IAPs and their antagonists in acute leukemias. The inhibitor of apoptosis protein family (IAP) The IAP is a family of proteins regulating the ac- tivity of the caspase cascade. They block both the Apoptosis · Vol 9 · No 6 · 2004 705