Topoisomerase II (
Topo II) inhibitors are cell cycle-specific
DNA-damaging agents and often correlate with secondary
leukemia with
chromosomal translocations involving the mixed-lineage
leukemia/myeloid lymphoid leukemia (MLL) gene on chromosome 11 band q23 (11q23). In spite of the clinical importance, the molecular mechanism for this
chromosomal translocation has yet to be elucidated. In this study, we employed 2-color FISH and detected intracellular
chromosomal translocations induced by
etoposide treatment. Cells such as
ataxia-telangiectasia mutated-deficient fibroblasts and U2OS cells, in which the early G2/M checkpoint
after treatment with low concentrations of
etoposide has been lost, executed mitosis with
etoposide-induced
DNA double-strand breaks, and 2-color FISH signals located on either side of the MLL gene were segregated in the postmitotic G1 phase. Long-term culture of cells that had executed mitosis under
etoposide treatment showed frequent structural abnormalities of chromosome 11. These findings provide convincing evidence for
Topo II inhibitor-induced 11q23 translocation. Our study also suggests an important role of the early G2/M checkpoint in preventing fixation of
chromosomal abnormalities and reveals environmental and genetic risk factors for the development of chromosome 11 translocations, namely, low concentrations of
Topo II inhibitors and dysfunctional early G2/M checkpoint control.