ArticleProceedings of the National Academy of Sciences of the United States of America2012
Model for MLL translocations in therapy-related leukemia involving topoisomerase IIβ-mediated DNA strand breaks and gene proximity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 99 papers.
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Who cites it
99 citing papers in PubMed, 172 citations in OpenAlex.
- Article
- PDS5A and TOP2B cooperate for chromatin recruitment via CTCF.bioRxiv : the preprint server for biology · 2026Article
- Exploring the Role of Environmental Factors on Chromosomal Translocations Associated With Childhood Leukaemia.Cancer medicine · 2026Article
- Topoisomerase IIb binding delineates localized mutational processes and driver mutations in cancer genomes.Nature communications · 2025Article
- How chemotherapy shapes hematopoietic stem cells.Nature genetics · 2025Article
- Mutagenesis of Intrinsically Disordered Domain Impacts Topoisomerase IIα Catalytic Activity.International journal of molecular sciences · 2025Article
- Topoisomerase II DNA Cleavage Assay Using Fluorescently Labelled Double-Stranded Oligonucleotides.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Toward a Unified Theory of Why Young People Develop Cancer.Cold Spring Harbor perspectives in medicine · 2024Review
- Highly sensitive mapping of in vitro type II topoisomerase DNA cleavage sites with SHAN-seq.Nucleic acids research · 2024Article
- Myeloperoxidase inhibition protects bone marrow mononuclear cells from DNA damage induced by the TOP2 poison anti-cancer drug etoposide.FEBS open bio · 2024Article
- Bioinformatic Analysis of Topoisomerase IIα Reveals Interdomain Interdependencies and Critical C-Terminal Domain Residues.International journal of molecular sciences · 2024Article
- Highly sensitive mapping ofbioRxiv : the preprint server for biology · 2024Article
- Use of CRISPR/Cas9 with Homology-Directed Repair to Gene-Edit Topoisomerase IIThe Journal of pharmacology and experimental therapeutics · 2024Article
- Mapping catalytically engaged TOP2B in neurons reveals the principles of topoisomerase action within the genome.Cell reports · 2024Article
- ATM inhibitor KU60019 synergistically sensitizes lung cancer cells to topoisomerase II poisons by multiple mechanisms.Scientific reports · 2023Article
- DNA fragility at theOpen biology · 2023Review
- Untangling the roles of TOP2A and TOP2B in transcription and cancer.Science advances · 2022Review
- Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy.Molecules (Basel, Switzerland) · 2022Article
- Single-cell diploid Hi-C reveals the role of spatial aggregations in complex rearrangements and KMT2A fusions in leukemia.Genome biology · 2022Article
- Human topoisomerases and their roles in genome stability and organization.Nature reviews. Molecular cell biology · 2022Review
39 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 4 countries.
Funding
Abstract
Topoisomerase poisons such as the epipodophyllotoxin etoposide are widely used effective cytotoxic anticancer agents. However, they are associated with the development of therapy-related acute myeloid leukemias (t-AMLs), which display characteristic balanced chromosome translocations, most often involving the mixed lineage leukemia (MLL) locus at 11q23. MLL translocation breakpoints in t-AMLs cluster in a DNase I hypersensitive region, which possesses cryptic promoter activity, implicating transcription as well as topoisomerase II activity in the translocation mechanism. We find that 2-3% of MLL alleles undergoing transcription do so in close proximity to one of its recurrent translocation partner genes, AF9 or AF4, consistent with their sharing transcription factories. We show that most etoposide-induced chromosome breaks in the MLL locus and the overall genotoxicity of etoposide are dependent on topoisomerase IIβ, but that topoisomerase IIα and -β occupancy and etoposide-induced DNA cleavage data suggest factors other than local topoisomerase II concentration determine specific clustering of MLL translocation breakpoints in t-AML. We propose a model where DNA double-strand breaks (DSBs) introduced by topoisomerase IIβ into pairs of genes undergoing transcription within a common transcription factory become stabilized by antitopoisomerase II drugs such as etoposide, providing the opportunity for illegitimate end joining and translocation.
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