Topoisomerase II and the etiology of chromosomal translocations.
Acute leukemias with balanced chromosomal translocations, protean morphologic and immunophenotypic presentations but generally shorter latency and absence of myelodysplasia are recognized as a complication of anti-cancer drugs that behave as topoisomerase II poisons. Translocations affecting the breakpoint cluster region of the MLL gene at chromosome band 11q23 are the most common molecular genetic aberrations in leukemias associated with the topoisomerase II poisons. These agents perturb the cleavage-religation equilibrium of topoisomerase II and increase cleavage complexes. One model suggests that this damages the DNA directly and leads to chromosomal breakage, which may result in untoward DNA recombination in the form of translocations. This review will summarize the evidence for topoisomerase II involvement in the genesis of translocations and extension of the model to acute leukemia in infants characterized by similar MLL translocations.
Felix
Carolyn A
CA
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. felix@email.chop.edu
Kolaris
Christos P
CP
Osheroff
Neil
N
D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001483:Base Sequence; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000139:chemically induced / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics*; D011995:Recombination, Genetic; D059005:Topoisomerase II Inhibitors; D014178:Translocation, Genetic
D000903:Antibiotics, Antineoplastic; C497422:KMT2A protein, human; D059005:Topoisomerase II Inhibitors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D004250:DNA Topoisomerases, Type II