Role of apoptotic nuclease caspase-activated DNase in etoposide-induced treatment-related acute myelogenous leukemia

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2006-09, Vol.66 (18), p.8975-8979
Main Authors: Hars, Eszter S, Lyu, Yi Lisa, Lin, Chao-Po, Liu, Leroy F
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents, Phytogenic - pharmacology
Apoptosis - physiology
Deoxyribonucleases - antagonists & inhibitors
Deoxyribonucleases - metabolism
Etoposide - pharmacology
Gene Rearrangement - drug effects
HT29 Cells
Humans
Leukemia, Myeloid, Acute - chemically induced
Leukemia, Myeloid, Acute - enzymology
Mice
Mice, Knockout
Myeloid-Lymphoid Leukemia Protein - genetics
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-06-1724