MOLECULAR PATHOGENESIS OF SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA

Abstract

<p>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 <em>PML</em> and <em>RARA</em> 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 the nature of the drug exposure. Remarkably, in approximately half of t-APL cases arising following mitoxantrone treatment for breast carcinoma or multiple sclerosis, the chromosome 15 breakpoint fell within an 8-bp “hotspot” region in <em>PML</em> 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 <em>RARA</em> breakpoints were also shown to be functional topoII cleavage sites. The observation that particular regions of the <em>PML </em>and <em>RARA </em>loci are susceptible to topoII-mediated DNA damage induced by epirubicin and mitoxantrone may underlie the propensity of these agents to cause APL.</p> <p> </p>

Keywords

• Leukemia, therapy related leukemia, Acute promyelocytic leukemia