Abstract
Treatment-related acute myeloid leukemia (t-AML) following successful therapy of a primary malignancy has been recognized with increasing frequency among cancer survivors over the past several years. Many of these t-AML cases are associated with the use of intensive chemotherapy regimens that employ one or more agents which target eukaryotic topoisomerase II (topo II), and demonstrate non-random chromosomal translocations involving either the MLL (ALL-1, HRX) gene at 11q23 or the AML1 gene at 21q22. Although many investigators have speculated that these translocations are induced by the therapeutic use of topo II inhibitors, the molecular sequence of events by which topo II inhibitors might induce a chromosomal translocation are not well understood. We describe here the reproducible induction of highly specific, double-strand DNA cleavage at a specific site within the AML1 locus by topo II inhibitors. This DNA cleavage, which maps to a region of the AML1 locus frequently disrupted by chromosomal translocations, can be induced in several cell lines, with multiple different topo II inhibitors, indicating that this phenomenon is not restricted to a specific cell type or specific topo II inhibitor. It is conceivable that site-specific double-strand DNA cleavage within the AML1 locus induced by topo II inhibitors represents the initial molecular event leading to a chromosomal translocation and t-AML.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Stanulla, M., Wang, J., Chervinsky, D. et al. Topoisomerase II inhibitors induce DNA double-strand breaks at a specific site within the AML1 locus. Leukemia 11, 490–496 (1997). https://doi.org/10.1038/sj.leu.2400632
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2400632
Keywords
This article is cited by
-
DNA damage accumulation and repair defects in acute myeloid leukemia: implications for pathogenesis, disease progression, and chemotherapy resistance
Chromosoma (2014)
-
Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients
Leukemia (2007)
-
Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML
Leukemia (2004)
-
Origins of chromosome translocations in childhood leukaemia
Nature Reviews Cancer (2003)
-
Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities
Leukemia (2002)