Aplan P D, Chervinsky D S, Stanulla M, Burhans W C
Department of Molecular Medicine and Pedriatrics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Blood. 1996 Apr 1;87(7):2649-58.
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.
位于11q23的MLL基因在多种新诊断的急性白血病中经常因染色体易位而被破坏。最近，很明显，在接受包含拓扑异构酶II抑制剂的化疗方案的继发性白血病患者中，MLL基因也经常因染色体易位而被破坏。这些与拓扑异构酶II抑制剂（最常见的是替尼泊苷、依托泊苷或阿霉素）相关的继发性白血病具有独特的临床和生物学特征，这引发了它们是由拓扑异构酶II抑制剂治疗诱导的推测。我们在MLL断裂点簇区域（bcr）内确定了一个对拓扑异构酶II抑制剂诱导的双链DNA切割高度敏感的位点。这一发现非常特异且高度可重复。尽管它最初是在从接受多药化疗的患者中分离出的恶性淋巴母细胞中发现的，但这种位点特异性双链DNA切割在组织培养中也可以使用恶性细胞系以及正常个体的外周血诱导产生。使用多种模型系统，位点特异性切割在相当一部分细胞中发生，具有时间和剂量依赖性，并且可以用阿霉素或依托泊苷诱导。这种位点特异性切割与MLL bcr内的一个共有拓扑异构酶II切割位点位于同一区域。这些结果表明，拓扑异构酶II抑制剂诱导的MLL bcr内的位点特异性切割可能是导致MLL易位和继发性白血病的早期步骤。
