{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:03:43Z","timestamp":1790744623827,"version":"4.1.0"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"17","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,8,14]]},"abstract":"<jats:p>\n                    We analyzed the der(11) and der(4) genomic breakpoint junctions of\n a t(4;11) in the leukemia of a patient previously administered\n etoposide and dactinomycin by molecular and biochemical approaches to\n gain insights about the translocation mechanism and the relevant drug\n exposure. The genomic breakpoint junctions were amplified by PCR.\n Cleavage of DNA substrates containing the normal homologues of the\n                    <jats:italic>MLL<\/jats:italic>\n                    and\n                    <jats:italic>AF-4<\/jats:italic>\n                    translocation breakpoints\n was examined\n                    <jats:italic>in vitro<\/jats:italic>\n                    upon incubation with human DNA\n topoisomerase II\u03b1 and etoposide, etoposide catechol, etoposide\n quinone, or dactinomycin. The der(11) and der(4) genomic breakpoint\n junctions both involved\n                    <jats:italic>MLL<\/jats:italic>\n                    intron 6 and\n                    <jats:italic>AF-4<\/jats:italic>\n                    intron 3. Recombination was precise at the sequence\n level except for the overall gain of a single templated nucleotide. The\n translocation breakpoints in\n                    <jats:italic>MLL<\/jats:italic>\n                    and\n                    <jats:italic>AF-4<\/jats:italic>\n                    were DNA topoisomerase II cleavage sites. Etoposide and its\n metabolites, but not dactinomycin, enhanced cleavage at these sites.\n Assuming that DNA topoisomerase II was the mediator of the breakage,\n processing of the staggered nicks induced by DNA topoisomerase II,\n including exonucleolytic deletion and template-directed polymerization,\n would have been required before ligation of the ends to generate the\n observed genomic breakpoint junctions. These data are inconsistent with\n a translocation mechanism involving interchromosomal recombination by\n simple exchange of DNA topoisomerase II subunits and DNA-strand\n transfer; however, consistent with reciprocal DNA topoisomerase II\n cleavage events in\n                    <jats:italic>MLL<\/jats:italic>\n                    and\n                    <jats:italic>AF-4<\/jats:italic>\n                    in which\n both breaks became stable, the DNA ends were processed and underwent\n ligation. Etoposide and\/or its metabolites, but not dactinomycin,\n likely were the relevant exposures in this patient.\n                  <\/jats:p>","DOI":"10.1073\/pnas.171309898","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:34:10Z","timestamp":1027679650000},"page":"9802-9807","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":71,"title":["Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at\n                    <i>MLL<\/i>\n                    and\n                    <i>AF-4<\/i>\n                    genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation"],"prefix":"10.1073","volume":"98","author":[{"given":"Brian D.","family":"Lovett","sequence":"first","affiliation":[{"name":"Division of Oncology, Joseph Stokes, Jr., Research\r Institute, Children's Hospital of Philadelphia, Philadelphia, PA\r 19104; Center for Cancer Pharmacology, University of\r Pennsylvania Cancer Center, and Departments of Pathology\r and Laboratory Medicine and Pediatrics, University of Pennsylvania\r School of Medicine, Philadelphia, PA 19104; and\r Department of Biochemistry, Vanderbilt University School\r of Medicine, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Lo Nigro","sequence":"additional","affiliation":[{"name":"Division of Oncology, Joseph Stokes, Jr., Research\r Institute, Children's Hospital of Philadelphia, Philadelphia, PA\r 19104; Center for Cancer Pharmacology, University of\r Pennsylvania Cancer Center, and Departments of Pathology\r and Laboratory Medicine and Pediatrics, University of Pennsylvania\r School of Medicine, Philadelphia, PA 19104; and\r Department of Biochemistry, Vanderbilt University School\r of Medicine, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric F.","family":"Rappaport","sequence":"additional","affiliation":[{"name":"Division of Oncology, Joseph Stokes, Jr., Research\r Institute, Children's Hospital of Philadelphia, Philadelphia, PA\r 19104; Center for Cancer Pharmacology, University of\r Pennsylvania Cancer Center, and Departments of Pathology\r and Laboratory Medicine and Pediatrics, University of Pennsylvania\r School of Medicine, Philadelphia, PA 19104; and\r Department of Biochemistry, Vanderbilt University School\r of Medicine, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A.","family":"Blair","sequence":"additional","affiliation":[{"name":"Division of Oncology, Joseph Stokes, Jr., Research\r Institute, Children's Hospital of Philadelphia, Philadelphia, PA\r 19104; Center for Cancer Pharmacology, University of\r Pennsylvania Cancer Center, and Departments of Pathology\r and Laboratory Medicine and Pediatrics, University of Pennsylvania\r School of Medicine, Philadelphia, PA 19104; and\r Department of Biochemistry, Vanderbilt University School\r of Medicine, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Osheroff","sequence":"additional","affiliation":[{"name":"Division of Oncology, Joseph Stokes, Jr., Research\r Institute, Children's Hospital of Philadelphia, Philadelphia, PA\r 19104; Center for Cancer Pharmacology, University of\r Pennsylvania Cancer Center, and Departments of Pathology\r and Laboratory Medicine and Pediatrics, University of Pennsylvania\r School of Medicine, Philadelphia, PA 19104; and\r Department of Biochemistry, Vanderbilt University School\r of Medicine, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naiyu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Division of Oncology, Joseph Stokes, Jr., Research\r Institute, Children's Hospital of Philadelphia, Philadelphia, PA\r 19104; Center for Cancer Pharmacology, University of\r Pennsylvania Cancer Center, and Departments of Pathology\r and Laboratory Medicine and Pediatrics, University of Pennsylvania\r School of Medicine, Philadelphia, PA 19104; and\r Department of Biochemistry, Vanderbilt University School\r of Medicine, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen D.","family":"Megonigal","sequence":"additional","affiliation":[{"name":"Division of Oncology, Joseph Stokes, Jr., Research\r Institute, Children's Hospital of Philadelphia, Philadelphia, PA\r 19104; Center for Cancer Pharmacology, University of\r Pennsylvania Cancer Center, and Departments of Pathology\r and Laboratory Medicine and Pediatrics, University of Pennsylvania\r School of Medicine, Philadelphia, PA 19104; and\r Department of Biochemistry, Vanderbilt University School\r of Medicine, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy Reed","family":"Williams","sequence":"additional","affiliation":[{"name":"Division of Oncology, Joseph Stokes, Jr., Research\r Institute, Children's Hospital of Philadelphia, Philadelphia, PA\r 19104; Center for Cancer Pharmacology, University of\r Pennsylvania Cancer Center, and Departments of Pathology\r and Laboratory Medicine and Pediatrics, University of Pennsylvania\r School of Medicine, Philadelphia, PA 19104; and\r Department of Biochemistry, Vanderbilt University School\r of Medicine, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"Nowell","sequence":"additional","affiliation":[{"name":"Division of Oncology, Joseph Stokes, Jr., Research\r Institute, Children's Hospital of Philadelphia, Philadelphia, PA\r 19104; Center for Cancer Pharmacology, University of\r Pennsylvania Cancer Center, and Departments of Pathology\r and Laboratory Medicine and Pediatrics, University of Pennsylvania\r School of Medicine, Philadelphia, PA 19104; and\r Department of Biochemistry, Vanderbilt University School\r of Medicine, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn A.","family":"Felix","sequence":"additional","affiliation":[{"name":"Division of Oncology, Joseph Stokes, Jr., Research\r Institute, Children's Hospital of Philadelphia, Philadelphia, PA\r 19104; Center for Cancer Pharmacology, University of\r Pennsylvania Cancer Center, and Departments of Pathology\r and Laboratory Medicine and Pediatrics, University of Pennsylvania\r School of Medicine, Philadelphia, PA 19104; and\r Department of Biochemistry, Vanderbilt University School\r of Medicine, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,8,7]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/88.7.407"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4781(98)00139-0"},{"key":"e_1_3_3_3_2","first-page":"137","volume-title":"Multiple Primary Cancers: Incidence, Etiology, Diagnosis and Prevention","author":"Felix C","year":"1999","unstructured":"C Felix Multiple Primary Cancers: Incidence, Etiology, Diagnosis and Prevention, eds A I Neugut, A T Meadows, E Robinson (Williams & Wilkins, Baltimore), pp. 137\u2013164 (1999)."},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/mpo.1125"},{"key":"e_1_3_3_5_2","first-page":"578","volume-title":"American Society of Clinical Oncology 2001 Educational Book","author":"Felix C A","year":"2001","unstructured":"C A Felix, M D Megonigal American Society of Clinical Oncology 2001 Educational Book, ed M C Perry (Am. 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