{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T06:51:39Z","timestamp":1793429499225,"version":"4.5.0"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,6,5]]},"abstract":"<jats:p>\n                    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 (\n                    <jats:italic>MLL<\/jats:italic>\n                    ) locus at 11q23.\n                    <jats:italic>MLL<\/jats:italic>\n                    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\u20133% of\n                    <jats:italic>MLL<\/jats:italic>\n                    alleles undergoing transcription do so in close proximity to one of its recurrent translocation partner genes,\n                    <jats:italic>AF9<\/jats:italic>\n                    or\n                    <jats:italic>AF4<\/jats:italic>\n                    , consistent with their sharing transcription factories. We show that most etoposide-induced chromosome breaks in the\n                    <jats:italic>MLL<\/jats:italic>\n                    locus and the overall genotoxicity of etoposide are dependent on topoisomerase II\u03b2, but that topoisomerase II\u03b1 and -\u03b2 occupancy and etoposide-induced DNA cleavage data suggest factors other than local topoisomerase II concentration determine specific clustering of\n                    <jats:italic>MLL<\/jats:italic>\n                    translocation breakpoints in t-AML. We propose a model where DNA double-strand breaks (DSBs) introduced by topoisomerase II\u03b2 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1204406109","type":"journal-article","created":{"date-parts":[[2012,5,21]],"date-time":"2012-05-21T23:03:58Z","timestamp":1337641438000},"page":"8989-8994","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":159,"title":["Model for\n                    <i>MLL<\/i>\n                    translocations in therapy-related leukemia involving topoisomerase II\u03b2-mediated DNA strand breaks and gene proximity"],"prefix":"10.1073","volume":"109","author":[{"given":"Ian G.","family":"Cowell","sequence":"first","affiliation":[{"name":"Institute for Cellular and Molecular Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zbyslaw","family":"Sondka","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayleigh","family":"Smith","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ka Cheong","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catriona M.","family":"Manville","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Sidorczuk-Lesthuruge","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly Ashlene","family":"Rance","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay","family":"Padget","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Northumbria University, Newcastle upon Tyne, NE1 8ST, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham Hunter","family":"Jackson","sequence":"additional","affiliation":[{"name":"Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noritaka","family":"Adachi","sequence":"additional","affiliation":[{"name":"Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline A.","family":"Austin","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,5,21]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.10.035"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.03.016"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1591"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(06)00412-X"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00695-4"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2006.10.008"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.002"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.10040"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V82.12.3705.3705"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2009.01.023"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-07-2527"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M803936200"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306500200"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.11.1671"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209948"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2883"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.3.195"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.10.031"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2010.11.001"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050192"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1127196"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1147674"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.613"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01576-07"},{"key":"e_1_3_3_25_2","first-page":"653","article-title":"Evidence for the involvement of DNA topoisomerase II in neutrophil-granulocyte differentiation","volume":"1","author":"Francis GE","year":"1987","unstructured":"GE Francis, et al., Evidence for the involvement of DNA topoisomerase II in neutrophil-granulocyte differentiation. 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