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| Site-specific DNA cleavage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors |
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| Author(s): Aplan PD, Chervinsky DS, Stanulla M, Burhans WC |
| Source: BLOOD Volume: 87 Issue: 7 Pages: 2649-2658 Published: APR 1 1996 |
| Times Cited: 121 References: 42 |
| Abstract: The MLL gene located at 11q23 is frequently disrupted by chromosomal translocation in a wide spectrum of newly diagnosed acute leukemias, Recently, it has become apparent that the MLL gene is very frequently disrupted by chromosomal translocations in patients with secondary leukemias associated with chemotherapeutic regimens incorporating topoisomerase II inhibitors. These secondary leukemias associated with topoisomerase II inhibitors (most commonly teniposide, etoposide, or doxorubicin) 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 cluster 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 malignant lymphoblasts isolated from a patient receiving multiagent chemotherapy, this site-specific double-strand DNA cleavage can be induced in tissue culture using malignant cell lines as well as peripheral blood from normal individuals. Site-specific cleavage occurs in a significant fraction of cells using a variety of model systems, is both time and dose dependent, and can be induced with either doxorubicin or etoposide. This site-specific cleavage maps to the same region as a consensus topoisomerase II cleavage site within the MLL bcr. These results suggest that site specific cleavage within the MLL bcr induced by topoisomerase II inhibitors may be an early step leading to MLL translocations and secondary leukemia. (C) 1996 by The American Society of Hematology. |
| Document Type: Article |
| Language: English |
| Reprint Address: Aplan, PD (reprint author), ROSWELL PK CANC INST, DEPT PEDIAT, BUFFALO, NY 14263 USA |
Addresses:
1. ROSWELL PK CANC INST, DEPT MOLEC MED, BUFFALO, NY 14263 USA
2. ROSWELL PK CANC INST, DEPT MOLEC & CELLULAR BIOL, BUFFALO, NY 14263 USA
3. HANNOVER MED SCH, DEPT PEDIAT, W-3000 HANNOVER, GERMANY |
| Publisher: W B SAUNDERS CO, INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 |
| Subject Category: Hematology |
| IDS Number: UC776 |
| ISSN: 0006-4971 |
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