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Role of Apoptotic Nuclease Caspase-Activated DNase in Etoposide-Induced Treatment-Related Acute Myelogenous Leukemia

Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey

Requests for reprints: Leroy F. Liu, Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. Phone: 732-235-4592; Fax: 732-235-4073; E-mail: lliu{at}umdnj.edu.

Etoposide-induced treatment-related acute myelogenous leukemia (t-AML) is characterized by rearrangements of the mixed lineage leukemia (MLL) gene with one of its >50 partner genes, most probably as a consequence of etoposide-induced DNA double-strand breaks (DSBs). Recent studies have shown that etoposide-induced DSBs occur predominantly within the breakpoint cluster region (bcr) of the MLL gene. However, bcr-specific DSBs induced by etoposide are not topoisomerase II–linked but the result of apoptotic nuclease–mediated DNA cleavage. Here, we test the involvement of caspase-activated DNase (CAD) and other apoptotic components in etoposide-induced gene rearrangements using two methods. First, we measured the effect of etoposide on the integration frequency of a transfected plasmid. Etoposide strongly stimulated plasmid integration in CAD cDNA–complemented mouse embryonic fibroblasts (MEFs) but not in CAD knockout (KO) MEFs. Consistently, down-regulation of ICAD (inhibitor of CAD, also required for proper folding of CAD) in an HT29-derived cell line, which leads to decreased CAD activity, significantly reduced etoposide-induced plasmid integration. Second, we used long-template inverse PCR to focus on gene rearrangements at the MLL locus. Etoposide stimulated MLL fusion product formation in CAD cDNA–complemented MEFs but not in CAD KO MEFs. Together, these results suggest that CAD and other apoptotic components may play an important role in etoposide-induced t-AML. (Cancer Res 2006; 66(18): 8975-9)

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