Abstract
Treatment with etoposide (VP-16) has been associated with translocation of the mixed lineage leukaemia (MLL) gene seen in treatment-related acute myeloid leukaemia (t-AML). Among the different partner genes, AF9 is the most common partner gene of MLL. AF9 shares similar structural element with the MLL gene. Various mechanisms of translocation have been proposed for the MLL gene, including apoptosis, particularly the apoptotic nuclease. In the current study, we show that VP-16 induced cleavage of the AF9 gene in both leukaemic cells and cultured normal blood cell. All the breakpoints were mapped within the BCR1 of the AF9 gene. AF9 cleavages in leukaemic cells were abolished by pre-treatment with caspase inhibitor (Z-DEVD-FMK), suggesting the involvement of caspase-activated DNase (CAD). The absence of AF9 cleavage in K562 cells further supported the involvement of apoptosis. However, AF9 cleavages in cultured normal blood cell were not eliminated by caspase inhibitor. The possible role of CAD and other apoptotic nucleases/effectors that could be involved in AF9 translocation are discussed.
Highlights
Etoposide (VP-16) is an epipodophyllotoxin that targets DNA topoisomerase II [1]
DNA sequencing shows that the 180 base pairs was an amplification product of an AF9 cleavage fragment that carries a breakpoint at coordinate 26805 (GenBank accession No AC000007), while the 730 base pairs corresponds to amplification of a cleaved AF9 fragment that carries a breakpoint at coordinate 26235 (GenBank accession No AC000007)
Treatment with etoposide (VP-16) has been correlated with translocation of the mixed lineage leukaemia (MLL) gene observed in treatment-related acute myeloid leukaemia (t-AML) patients [4,5]
Summary
Etoposide (VP-16) is an epipodophyllotoxin that targets DNA topoisomerase II [1]. Etoposide exerts its anticancer effects by “poisoning” topoisomerase II, resulting in DNA cleavages [1]. Translocation of the MLL gene is found in t-AML but in de novo leukaemia as well [6] In both cases, mapping of the chromosomal breakpoints in MLL revealed that almost all of the breakpoints clustered within an 8.3-kb region known as the breakpoint cluster region (BCR) [6]. This region contains a weak- and a high-affinity Scaffold Attachment Region (SAR) [6]
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