title: Model for MLL translocations in therapy-related leukemia involving topoisomerase IIβ-mediated DNA strand breaks and gene proximity.
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.
authors.affiliation: Institute for Cellular and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Cowell
authors.forename: Zbyslaw
authors.initials: Z
authors.lastname: Sondka
authors.forename: Kayleigh
authors.initials: K
authors.lastname: Smith
authors.forename: Ka Cheong
authors.initials: KC
authors.lastname: Lee
authors.forename: Catriona M
authors.initials: CM
authors.lastname: Manville
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Sidorczuk-Lesthuruge
authors.forename: Holly Ashlene
authors.initials: HA
authors.lastname: Rance
authors.forename: Kay
authors.initials: K
authors.lastname: Padget
authors.forename: Graham Hunter
authors.initials: GH
authors.lastname: Jackson
authors.forename: Noritaka
authors.initials: N
authors.lastname: Adachi
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Austin
mesh_terms: D047369:Chromatin Immunoprecipitation; D053903:DNA Breaks, Double-Stranded; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005047:Etoposide; D005453:Fluorescence; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D015162:Micronucleus Tests; D008954:Models, Biological; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D005047:Etoposide; D004250:DNA Topoisomerases, Type II