Reciprocal DNA topoisomerase II cleavage events at 5'-TATTA-3' sequences in MLL and AF-9 create homologous single-stranded overhangs that anneal to form der(11) and der(9) genomic breakpoint junctions in treatment-related AML without further processing.

Whitmarsh RJ, Saginario C, Zhuo Y, Hilgenfeld E, Rappaport EF, Megonigal MD, Carroll M, Liu M, Osheroff N, Cheung NK, Slater DJ, Ried T, Knutsen T, Blair IA, Felix CA
Oncogene. 2003 22 (52): 8448-59

PMID: 14627986 · DOI:10.1038/sj.onc.1207052

Few t(9;11) translocations in DNA topoisomerase II inhibitor-related leukemias have been studied in detail and the DNA damage mechanism remains controversial. We characterized the der(11) and der(9) genomic breakpoint junctions in a case of AML following etoposide and doxorubicin. Etoposide-, etoposide metabolite- and doxorubicin-induced DNA topoisomerase II cleavage was examined in normal homologues of the MLL and AF-9 breakpoint sequences using an in vitro assay. Induction of DNA topoisomerase II cleavage complexes in CEM and K562 cell lines was investigated using an in vivo complex of enzyme assay. The translocation occurred between identical 5'-TATTA-3' sequences in MLL intron 8 and AF-9 intron 5 without the gain or loss of bases. The 5'-TATTA-3' sequences were reciprocally cleaved by DNA topoisomerase II in the presence of etoposide, etoposide catechol or etoposide quinone, creating homologous 4-base 5' overhangs that would anneal to form both breakpoint junctions without any processing. der(11) and der(4) translocation breakpoints in a treatment-related ALL at the same site in MLL are consistent with a damage hotspot. Etoposide and both etoposide metabolites induced DNA topoisomerase II cleavage complexes in the hematopoietic cell lines. These results favor the model in which the chromosomal breakage leading to MLL translocations in DNA topoisomerase II inhibitor-related leukemias is a consequence of DNA topoisomerase II cleavage.

MeSH Terms (16)

Adolescent DNA-Binding Proteins DNA Topoisomerases, Type II Histone-Lysine N-Methyltransferase Humans In Situ Hybridization, Fluorescence Leukemia, Myeloid, Acute Male Molecular Sequence Data Myeloid-Lymphoid Leukemia Protein Nuclear Proteins Protein Processing, Post-Translational Proto-Oncogenes Recombination, Genetic Transcription Factors Translocation, Genetic

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