title: DNA topoisomerase II in therapy-related acute promyelocytic leukemia.
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.
authors.affiliation: Department of Medical and Molecular Genetics, Guy's, King's, and St. Thomas' School of Medicine, London.
authors.forename: Anita R
authors.initials: AR
authors.lastname: Mistry
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Felix
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Whitmarsh
authors.forename: Annabel
authors.initials: A
authors.lastname: Mason
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.forename: Bruno
authors.initials: B
authors.lastname: Cassinat
authors.forename: Anne
authors.initials: A
authors.lastname: Parry
authors.forename: Christoph
authors.initials: C
authors.lastname: Walz
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
authors.forename: Mark R
authors.initials: MR
authors.lastname: Segal
authors.forename: Lionel
authors.initials: L
authors.lastname: Adès
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.forename: Neil
authors.initials: N
authors.lastname: Osheroff
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peniket
authors.forename: Marina
authors.initials: M
authors.lastname: Lafage-Pochitaloff
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
authors.forename: Ellen
authors.initials: E
authors.lastname: Solomon
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D004317:Doxorubicin / Q000009:adverse effects; D005047:Etoposide / Q000009:adverse effects; D006801:Humans; D066298:In Vitro Techniques; D015473:Leukemia, Promyelocytic, Acute / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D008942:Mitoxantrone / Q000494:pharmacology; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D059005:Topoisomerase II Inhibitors; D014178:Translocation, Genetic
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004317:Doxorubicin; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II