Mistry AR et al. (2005) DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med 352: 1529–1538

Development of acute myeloid leukemia (AML) is often associated with reciprocal balanced chromosomal translocations. Chemotherapeutic agents that poison topoisomerase II—for example, mitoxantrone—have been implicated in this process. An international study by Mistry et al. has now shown that topoisomerase II is directly involved in formation of the t(15;17) chromosomal translocation, in patients with chemotherapy-related acute promyelocytic leukemia (APL)—one of the commonest forms of AML. The t(15;17) is the most frequent translocation in APL, and disrupts the PML and RARA genes giving rise to the PML-RARα oncoprotein.

The study included six patients who developed APL following mitoxantrone-based treatment for breast carcinoma or multiple sclerosis. The genomic breakpoints in PML and RARA were characterized using long-range polymerase chain reaction and DNA sequence analysis. In four of the patients, the translocation breakpoints were tightly clustered in an 8-base pair region of intron 6 of the PML gene; this clustering was unlikely to have arisen by chance and so was suggestive of a 'hot spot' of DNA damage.

Next, the normal homologue of this translocation breakpoint hot spot was analyzed using functional in vitro topoisomerase II cleavage assays. This revealed that topoisomerase II-mediated cleavage at this site was enhanced 9-fold by exposure to mitoxantrone. The corresponding RARA breakpoints were also matched to mitoxantrone-induced sites of cleavage by topoisomerase II.

These observations also applied to patients who had been treated with etoposide or doxorubicin, suggesting that treatment with other topoisomerase II poisons can lead to the observed topoisomerase II-mediated cleavage of DNA in therapy-related APL.