%0 Journal Article
%T MOLECULAR PATHOGENESIS OF SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA
%A Melanie Joannides
%A Ashley N Mays
%A Anita R Mistry
%A Syed Khizer Hasan
%J Mediterranean Journal of Hematology and Infectious Diseases
%D 2011
%I 
%R 10.4084/mjhid.2011.
%X 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 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 ˇ°hotspotˇ± 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 ˇ°hotspotˇ±, 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.
%K Leukemia
%K therapy related leukemia
%K Acute promyelocytic leukemia
%U http://www.mjhid.org/article/view/9085