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Papers In Press, published online ahead of print June 13, 2001
Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854
Corresponding Author: lliu{at}umdnj.edu
VP-16 (etoposide) has recently been shown to induce topoisomerase II (TOP2)-mediated DNA cleavage within the MLL (mixed lineage leukemia) bcr (breakpoint cluster region), suggesting a role of TOP2 in MLL gene rearrangement. In our current studies, we have compared the induction of DNA cleavage within the MLL bcr in different cell lines after treatment with various anticancer drugs. All anticancer drugs tested including VP-16 (a TOP2-directed drug), camptothecin (a TOP1-directed drug), 5-fluorouracil and methotrexate (antimetabolites), and vinblastine (a microtubule inhibitor), induced the same site-specific cleavage within the MLL bcr. This cleavage was shown to be nuclease- but not TOP2-mediated by the following observations: (1) Drug-induced cleavage within the MLL bcr was not protein-linked. (2) Unlike TOP2-mediated cleavage, drug-induced DNA cleavage within the MLL bcr was kinetically slow, and coincided with the formation of the apoptotic nucleosomal DNA ladder. (3) Drug-induced cleavage within the MLL bcr was unaffected in cells with reduced nuclear TOP2. (4) Drug-induced cleavage within the MLL bcr was abolished by the caspase inhibitor, Z-DEVD-FMK. The possibility that an apoptotic nuclease may be involved in cleavage of the MLL bcr and MLL gene translocation is discussed.
J. Biol. Chem, 10.1074/jbc.M103962200
Submitted on May 2, 2001
Revised on June 12, 2001
Accepted on June 12, 2001
Nucleolytic cleavage of the MLL breakpoint cluster region (bcr) during apoptosis
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