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Model for MLL translocations in therapy-related leukemia involving topoisomerase IIβ-mediated DNA strand breaks and gene proximity

Lookup NU author(s): Dr Ian CowellORCiD, Dr Zbyslaw Sondka, Kayleigh Smith, Ka Lee, Catriona Manville, Malgorzata Sidorczuk-Lesthurge, Holly Rance, Dr Kay Padget, Professor Graham Jackson, Professor Caroline AustinORCiD



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 II beta, but that topoisomerase II alpha and -beta 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 II beta into pairs of genes undergoing transcription within a common transcription factory become stabilized by anti-topoisomerase II drugs such as etoposide, providing the opportunity for illegitimate end joining and translocation.

Publication metadata

Author(s): Cowell IG, Sondka Z, Smith K, Lee KC, Manville CM, Sidorczuk-Lesthuruge M, Rance HA, Padget K, Jackson GH, Adachi N, Austin CA

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences

Year: 2012

Volume: 109

Issue: 23

Pages: 8989-8994

Print publication date: 01/06/2012

Date deposited: 08/08/2012

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences


DOI: 10.1073/pnas.1204406109


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Funder referenceFunder name
07065Leukaemia and Lymphoma Research
07038Leukaemia and Lymphoma Research
BB/E528460/1Biotechnology and Biological Sciences Research Council
BB/G529383/1Biotechnology and Biological Sciences Research Council