Etoposide and illegitimate DNA double-strand break repair in the generation of MLL translocations: new insights and new questions

DNA Repair (Amst). 2006 Sep 8;5(9-10):1109-18. doi: 10.1016/j.dnarep.2006.05.018. Epub 2006 Jun 30.


Faithful repair of chromosomal double-strand breaks (DSBs) is central to genome integrity and the suppression of genome rearrangements including translocations that are a hallmark of leukemia, lymphoma, and soft-tissue sarcomas [B. Elliott, M. Jasin, Double-strand breaks and translocations in cancer, Cell. Mol. Life Sci. 59 (2002) 373-385; D.C. van Gent, J.H. Hoeijmakers, R. Kanaar, Chromosomal stability and the DNA double-stranded break connection, Nat. Rev. Genet. 2 (2001) 196-206]. Chemotherapy agents that target the essential cellular enzyme topoisomerase II (topo II) are known promoters of DSBs and are associated with therapy-related leukemias. There is a clear clinical association between previous exposure to etoposide and therapy-related acute myeloid leukemia (t-AML) characterized by chromosomal rearrangements involving the mixed lineage leukemia (MLL) gene on chromosome band 11q23 [C.A. Felix, Leukemias related to treatment with DNA topoisomerase II inhibitors, Med. Pediatr. Oncol. 36 (2001) 525-535]. Most MLL rearrangements initiate within a well-characterized 8.3 kb region that contains both putative topo II cleavage recognition sequences and repetitive elements leading to the logical hypothesis that MLL is particularly susceptible to aberrant cleavage and homology-mediated fusion to repetitive elements located on novel chromosome partners. In this review, we will discuss the findings and implications of recent attempts to confirm this hypothesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents, Phytogenic / adverse effects*
  • Chromosome Breakage*
  • Chromosomes, Human, Pair 11
  • DNA Damage*
  • DNA Repair*
  • DNA Topoisomerases, Type II / genetics
  • Etoposide / adverse effects*
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Leukemia, Myeloid, Acute / chemically induced*
  • Leukemia, Myeloid, Acute / genetics
  • Models, Genetic
  • Myeloid-Lymphoid Leukemia Protein
  • Sensitivity and Specificity
  • Topoisomerase II Inhibitors*


  • Antineoplastic Agents, Phytogenic
  • KMT2A protein, human
  • Topoisomerase II Inhibitors
  • Myeloid-Lymphoid Leukemia Protein
  • Etoposide
  • Histone-Lysine N-Methyltransferase
  • DNA Topoisomerases, Type II