Molecular Pathogenesis of Secondary Acute

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 th leukemia (APL). An increasing proportion of APL cases are therapy 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 drug exposure. Remarkably, in approximately half of t mitoxantrone treatment for breast within an 8-bp “hotspot” region in topoII-mediated DNA cleavage induced by mitoxantrone. outside the “hotspot”, and the corresponding topoII cleavage sites. The observation t susceptible to topoII-mediated DNA damage induced by epirubicin and mitoxantrone may underlie the propensity of these agents to cause APL. Introduction. Acute myeloid leukemia (AML) is characterized by a spectrum of recurring chromosomal www.mjhid.org ISSN 2035-3006 Promyelocytic Leukemia , Syed Khizer Hasan, Andreas Reiter , Ellen Solomon and David Grimwade Fax: +44 207 188 2585. E eclared that no competing interests exist. 45, DOI 10.4084/MJHID.2011.045 the terms of the Creative Commons Attribution License ), which permits unrestricted use, distribution, and reproduction in any medium, e PML and RARA genes, giving rise to acute promyelocytic -related (t -APL cases arising following cancer or multiple sclerosis, the chromosome 15 breakpoint fell PML intron 6, which was confirmed to be a preferential site of Chromosome 15 breakpoints falling RARA breakpoints were also shown to be functional hat particular regions of the PML abnormalities, which distinguish biologically and prognostically distinct subtypes of disease (reviewed . , Joseph L Wiemels, 1