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Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation.

Lovett BD, Lo Nigro L, Rappaport EF, Blair IA, Osheroff N, Zheng N, Megonigal MD, Williams WR, Nowell PC, Felix CA
Proc Natl Acad Sci U S A. 2001 98 (17): 9802-7

PMID: 11493704 · PMCID: PMC55533 · DOI:10.1073/pnas.171309898

We analyzed the der(11) and der(4) genomic breakpoint junctions of a t(4;11) in the leukemia of a patient previously administered etoposide and dactinomycin by molecular and biochemical approaches to gain insights about the translocation mechanism and the relevant drug exposure. The genomic breakpoint junctions were amplified by PCR. Cleavage of DNA substrates containing the normal homologues of the MLL and AF-4 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha and etoposide, etoposide catechol, etoposide quinone, or dactinomycin. The der(11) and der(4) genomic breakpoint junctions both involved MLL intron 6 and AF-4 intron 3. Recombination was precise at the sequence level except for the overall gain of a single templated nucleotide. The translocation breakpoints in MLL and AF-4 were DNA topoisomerase II cleavage sites. Etoposide and its metabolites, but not dactinomycin, enhanced cleavage at these sites. Assuming that DNA topoisomerase II was the mediator of the breakage, processing of the staggered nicks induced by DNA topoisomerase II, including exonucleolytic deletion and template-directed polymerization, would have been required before ligation of the ends to generate the observed genomic breakpoint junctions. These data are inconsistent with a translocation mechanism involving interchromosomal recombination by simple exchange of DNA topoisomerase II subunits and DNA-strand transfer; however, consistent with reciprocal DNA topoisomerase II cleavage events in MLL and AF-4 in which both breaks became stable, the DNA ends were processed and underwent ligation. Etoposide and/or its metabolites, but not dactinomycin, likely were the relevant exposures in this patient.

MeSH Terms (35)

Antigens, Neoplasm Antineoplastic Combined Chemotherapy Protocols Catechols Child Chromosome Breakage Chromosomes, Human, Pair 4 Chromosomes, Human, Pair 11 Combined Modality Therapy Cyclophosphamide Dactinomycin DNA, Neoplasm DNA-Binding Proteins DNA Topoisomerases, Type II Etoposide Female Histone-Lysine N-Methyltransferase Humans Ifosfamide Isoenzymes Models, Genetic Molecular Sequence Data Myeloid-Lymphoid Leukemia Protein Neoplasm Proteins Neoplasms, Second Primary Nuclear Proteins Precursor Cell Lymphoblastic Leukemia-Lymphoma Proto-Oncogenes Radiotherapy, Adjuvant Recombination, Genetic Rhabdomyosarcoma, Alveolar Soft Tissue Neoplasms Transcriptional Elongation Factors Transcription Factors Translocation, Genetic Vincristine

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