Balanced
chromosomal translocations that generate chimeric
oncoproteins are considered to be initiating lesions in the pathogenesis of
acute myeloid leukemia. The most frequent is the t(15;17)(q22;q21), which fuses the PML and RARA genes, giving rise to
acute promyelocytic leukemia (APL). An increasing proportion of APL cases are
therapy-related (t-APL), which develop following exposure to
radiotherapy and/or chemotherapeutic agents that target
DNA topoisomerase II (topoII), particularly
mitoxantrone and
epirubicin. To gain insights into molecular mechanisms underlying the formation of the t(15;17) we mapped the translocation breakpoints in a series of t-APLs, which revealed significant clustering according to the nature of the drug exposure. Remarkably, in approximately half of t-APL cases arising following
mitoxantrone treatment for
breast cancer or
multiple sclerosis, the chromosome 15 breakpoint fell within an 8-bp "hotspot" region in PML intron 6, which was confirmed to be a preferential site of topoII-mediated DNA cleavage induced by
mitoxantrone. Chromosome 15 breakpoints falling outside the "hotspot", and the corresponding RARA breakpoints were also shown to be functional topoII cleavage sites. The observation that particular regions of the PML and RARA loci are susceptible to topoII-mediated DNA damage induced by
epirubicin and
mitoxantrone may underlie the propensity of these agents to cause APL.