SITE-SPECIFIC DNA CLEAVAGE WITHIN THE MLL BREAKPOINT CLUSTER REGION INDUCED BY TOPOISOMERASE-II INHIBITORS

The MLL gene located at 11q23 is frequently disrupted by chromosomal t ranslocation in a wide spectrum of newly diagnosed acute leukemias, Re cently, it has become apparent that the MLL gene is very frequently di srupted by chromosomal translocations in patients with secondary leuke mias associated with chemotherapeutic regimens incorporating topoisome rase II inhibitors. These secondary leukemias associated with topoisom erase II inhibitors (most commonly teniposide, etoposide, or doxorubic in) have distinct clinical and biologic features which have led to the speculation that they are induced by treatment with topoisomerase II inhibitors. We have identified a site within the MLL breakpoint cluste r region (bcr) that is highly sensitive to double-strand DNA cleavage induced by topoisomerase II inhibitors. This finding is quite specific and highly reproducible. Although it was initially discovered in mali gnant lymphoblasts isolated from a patient receiving multiagent chemot herapy, this site-specific double-strand DNA cleavage can be induced i n tissue culture using malignant cell lines as well as peripheral bloo d from normal individuals. Site-specific cleavage occurs in a signific ant fraction of cells using a variety of model systems, is both time a nd dose dependent, and can be induced with either doxorubicin or etopo side. This site-specific cleavage maps to the same region as a consens us topoisomerase II cleavage site within the MLL bcr. These results su ggest that site specific cleavage within the MLL bcr induced by topois omerase II inhibitors may be an early step leading to MLL translocatio ns and secondary leukemia. (C) 1996 by The American Society of Hematol ogy.