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: Anita R Mistry, Carolyn A Felix, Ryan J Whitmarsh, Annabel Mason, Andreas Reiter, Bruno Cassinat, Anne Parry, Christoph Walz, Joseph L Wiemels, Mark R Segal, Lionel Adès, Ian A Blair, Neil Osheroff, Andrew J Peniket, Marina Lafage-Pochitaloff, Nicholas C P Cross, Christine Chomienne, Ellen Solomon, Pierre Fenaux, David Grimwade
• Journal: The New England journal of medicine (N Engl J Med) Vol. 352 Issue 15 Pg. 1529-38 (Apr 14 2005) ISSN: 1533-4406 [Electronic] United States
• PMID: 15829534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2005 Massachusetts Medical Society.

Chemical References

• Antineoplastic Agents
• DNA, Neoplasm
• Topoisomerase II Inhibitors
• Etoposide
• Doxorubicin
• Mitoxantrone
• DNA Topoisomerases, Type II

Topics

• Antineoplastic Agents (adverse effects, pharmacology)
• DNA Damage
• DNA Repair
• DNA Topoisomerases, Type II (metabolism)
• DNA, Neoplasm (drug effects, metabolism)
• Doxorubicin (adverse effects)
• Etoposide (adverse effects)
• Humans
• In Vitro Techniques
• Leukemia, Promyelocytic, Acute (chemically induced, enzymology, genetics)
• Mitoxantrone (pharmacology)
• Neoplasms, Second Primary (chemically induced, enzymology, genetics)
• Polymerase Chain Reaction
• Sequence Analysis, DNA
• Topoisomerase II Inhibitors
• Translocation, Genetic