DNA topoisomerase II in therapy-related acute promyelocytic leukemia
| Autor: | Carolyn A. Felix, Neil Osheroff, Nicholas C.P. Cross, Bruno Cassinat, David Grimwade, Ryan J. Whitmarsh, Lionel Ades, Ian A. Blair, A Parry, Andrew Peniket, Annabel Mason, Marina Lafage-Pochitaloff, Joseph L. Wiemels, Pierre Fenaux, Andreas Reiter, Anita R. Mistry, Mark R. Segal, Christoph Walz, Ellen Solomon, Christine Chomienne |
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| Rok vydání: | 2005 |
| Předmět: |
Acute promyelocytic leukemia
DNA Repair DNA repair Chromosomal translocation Antineoplastic Agents In Vitro Techniques Polymerase Chain Reaction Translocation Genetic chemistry.chemical_compound Leukemia Promyelocytic Acute medicine Humans Topoisomerase II Inhibitors Etoposide Mitoxantrone biology Topoisomerase Neoplasms Second Primary General Medicine DNA Neoplasm Sequence Analysis DNA medicine.disease Molecular biology Leukemia DNA Topoisomerases Type II chemistry Doxorubicin biology.protein Topoisomerase-II Inhibitor DNA medicine.drug DNA Damage |
| Zdroj: | The New England journal of medicine. 352(15) |
| ISSN: | 1533-4406 |
| Popis: | 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.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.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.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. |
| Databáze: | OpenAIRE |
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