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Previous Volume 352:1529-1538 April 14, 2005 Number 15 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Editorial by Pedersen-Bjergaard, J. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Chromosomal translocations leading to chimeric oncoproteins are 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 laryngeal cancer with chemotherapeutic agents that poison topoisomerase II.

Methods We used long-range polymerase chain reaction and sequence analysis to characterize t(15;17) genomic breakpoints in therapy-related APL. To determine whether topoisomerase II was directly involved in mediating breaks of double-stranded DNA at the observed translocation breakpoints, we used a functional in vitro assay to examine topoisomerase II–mediated cleavage in the normal homologues of the PML and RARA breakpoints.

Results Translocation breakpoints in APL that developed after exposure to mitoxantrone, a topoisomerase II poison, were tightly clustered in an 8-bp region within PML intron 6. In functional assays, this "hot spot" and the corresponding RARA breakpoints were common sites of mitoxantrone-induced cleavage by topoisomerase II. Etoposide and doxorubicin also induced cleavage by topoisomerase II at the translocation breakpoints in APL arising after exposure to these agents. Short, homologous sequences in PML and RARA suggested the occurrence of DNA repair by means of the nonhomologous end-joining pathway.

Conclusions Drug-induced cleavage of DNA by topoisomerase II mediates the formation of chromosomal translocation breakpoints in mitoxantrone-related APL and in APL that occurs after therapy with 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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