DNA Topoisomerase II in Therapy-Related Acute Promyelocytic Leukemia
Anita R. Mistry, Ph.D., Carolyn A. Felix, M.D., Ryan J. Whitmarsh, B.A., Annabel Mason, B.Sc., Andreas Reiter, M.D., Bruno Cassinat, Pharm.D., Anne Parry, Ph.D., Christoph Walz, Joseph L. Wiemels, Ph.D., Mark R. Segal, Ph.D., Lionel Adès, M.D., Ian A. Blair, Ph.D., Neil Osheroff, Ph.D., Andrew J. Peniket, B.A., Marina Lafage-Pochitaloff, Ph.D., Nicholas C.P. Cross, Ph.D., Christine Chomienne, Ph.D., Ellen Solomon, Ph.D., Pierre Fenaux, Ph.D., and David Grimwade, Ph.D.
Background Chromosomal translocations leading to chimeric oncoproteinsare important in leukemogenesis, but how they form is unclear.We studied acute promyelocytic leukemia (APL) with the t(15;17)translocation that developed after treatment of breast or laryngealcancer with chemotherapeutic agents that poison topoisomeraseII.
Methods We used long-range polymerase chain reaction and sequenceanalysis to characterize t(15;17) genomic breakpoints in therapy-relatedAPL. To determine whether topoisomerase II was directly involvedin mediating breaks of double-stranded DNA at the observed translocationbreakpoints, we used a functional in vitro assay to examinetopoisomerase II–mediated cleavage in the normal homologuesof the PML and RARA breakpoints.
Results Translocation breakpoints in APL that developed afterexposure to mitoxantrone, a topoisomerase II poison, were tightlyclustered in an 8-bp region within PML intron 6. In functionalassays, this "hot spot" and the corresponding RARA breakpointswere common sites of mitoxantrone-induced cleavage by topoisomeraseII. Etoposide and doxorubicin also induced cleavage by topoisomeraseII at the translocation breakpoints in APL arising after exposureto these agents. Short, homologous sequences in PML and RARAsuggested the occurrence of DNA repair by means of the nonhomologousend-joining pathway.
Conclusions Drug-induced cleavage of DNA by topoisomerase IImediates the formation of chromosomal translocation breakpointsin mitoxantrone-related APL and in APL that occurs after therapywith other topoisomerase II poisons.
Source Information
From the Department of Medical and Molecular Genetics, Guy's, King's, and St. Thomas' School of Medicine, London (A.R.M., A.M., E.S., D.G.); the Division of Oncology, Children's Hospital of Philadelphia, Philadelphia (C.A.F., R.J.W.); the Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (C.A.F.); Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany (A.R., C.W.); Unité de Biologie Cellulaire, Service de Médecine Nucléaire, Hôpital St. Louis, Paris (B.C., A.P., C.C.); the Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco (J.L.W., M.R.S.); Hôpital Avicenne–Paris 13 Université, Bobigny, France (L.A., P.F.); the Center for Cancer Pharmacology, University of Pennsylvania, Philadelphia (I.A.B.); the Departments of Biochemistry and Medicine, Vanderbilt University School of Medicine, Nashville (N.O.); the Department of Haematology, John Radcliffe Hospital, Oxford, United Kingdom (A.J.P.); Institut Paoli-Calmettes, INSERM UMR 599, and Université de la Méditerranée, Marseille, France (M.L.-P.); Wessex Regional Genetics Laboratory, Salisbury, United Kingdom (N.C.P.C.); and the Department of Haematology, University College London Hospitals, London (D.G.).
Address reprint requests to Dr. Grimwade at the Cancer Genetics Laboratory, Department of Medical and Molecular Genetics, 8th Fl., Guy's Tower, Guy's Hospital, London SE1 9RT, United Kingdom, or at david.grimwade{at}genetics.kcl.ac.uk.
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