Translocation Mechanism in Secondary Leukemias Following Topoisomerase II
Poisons
Carolyn A. Felix1,2 Blaine W. Robinson1 Giuseppe Germano1 Christos P. Kolaris1
Leslie J. Raffini1*2,3 Luca Lo Nigro1*,4 Emily Roumm1* Maureen D. Megonigal1*
Diana J. Slater1* Ryan J. Whitmarsh1* Charles Saginario1*
Brian D. Lovett1* Jolanta Libura5 Linda D. Pegram1*
Naiyu Zheng6* Shaokun Pang6* Xiaoliang Zhou6* Eric F. Rappaport7 Christine A. Richardson5*,8 Nai-Kong V. Cheung9 Ian A. Blair6 Neil Osheroff 10
1Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; 2Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA; 3Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA; 4University of Catania, Catania, IT; 5Institute of Cancer Genetics, Department of Pathology, Columbia University College of Physicians and Surgeons; 6Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA; 7NAPCORE, Children's Hospital of Philadelphia, Philadelphia, PA; 8Department of Biology and Bioinformatics Research Center, University of North Carolina, Charlotte, NC; 9Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY; 10Departments of Biochemistry and Medicine, Vanderbilt University School of Medicine, Nashville, TN
(*indicates affiliation where work completed, not current affiliation)
More than 15 years after observations of an association between a distinct form of leukemia characterized by balanced chromosomal translocations involving band 11q23 and introduction of epipodophyllotoxins into clinical usage for anti-cancer treatment in the late1980s, the translocation mechanism is still debated. Epipodophyllotoxins and other anticancer drugs that have been linked to leukemias with various balanced translocations as a treatment complication share the property of being topoisomerase II poisons. In the early 1990s the MLL (ALL-1, HRX, hTRX1) gene was cloned by several groups at the genomic breakpoint junctions of translocations disrupting chromosome band 11q23. This paper will review evidence in favor of the hypothesis that topoisomerase II cleavage complexes induced by poisons of this enzyme damage DNA directly and lead to translocations in secondary leukemias with MLL translocations.
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