Strissel P L, Strick R, Rowley J D, Zeleznik-Le N J
Department of Medicine, University of Chicago, Chicago, IL, USA.
Blood. 1998 Nov 15;92(10):3793-803.
The human myeloid-lymphoid leukemia gene, MLL (also called ALL-1, Htrx, or HRX ), maps to chromosomal band 11q23. MLL is involved in translocations that result in de novo acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), mixed lineage leukemia, and also in therapy AML (t-AML) and therapy ALL (t-ALL) resulting from treatment with DNA topoisomerase II (topo II) targeting drugs. MLL can recombine with more than 30 other chromosomal bands, of which 16 of the partner genes have been cloned. Breaks in MLL occur in an 8. 3-kb breakpoint cluster region (BCR) encompassing exons 5 through 11. We recently demonstrated that 75% of de novo patient breakpoints in MLL mapped in the centromeric half of the BCR between two scaffold-associated regions (SAR), whereas 75% of the t-AML patient breakpoints mapped to the telomeric half of the BCR within a strong SAR. We have mapped additional structural elements in the BCR. An in vivo DNA topo II cleavage site (induced with several different drugs that target topo II) mapped near exon 9 in three leukemia cell lines. A strong DNase I hypersensitive site (HS) also mapped near exon 9 in four leukemia cell lines, including two in which MLL was rearranged [a t(6;11) and a t(9;11)], and in two lymphoblastoid cell lines with normal MLL. Two of the leukemia cell lines also showed an in vivo topo II cleavage site. Our results suggest that the chromatin structure of the MLL BCR may influence the location of DNA breaks in both de novo and therapy-related leukemias. We propose that topo II is enriched in the MLL telomeric SAR and that it cleaves the DNase I HS site after treatment with topo II inhibitors. These events may be involved in recombination associated with t-AML/t-ALL breakpoints mapping in the MLL SAR.
人类髓系-淋巴系白血病基因MLL（也称为ALL-1、Htrx或HRX）定位于染色体11q23带。MLL参与导致原发性急性淋巴细胞白血病（ALL）、急性髓性白血病（AML）、混合谱系白血病的易位，也参与由靶向DNA拓扑异构酶II（拓扑II）的药物治疗引起的治疗相关性AML（t-AML）和治疗相关性ALL（t-ALL）。MLL可与30多个其他染色体带发生重组，其中16个伙伴基因已被克隆。MLL的断裂发生在一个8.3kb的断点簇区域（BCR），该区域包含外显子5至11。我们最近证明，原发性患者MLL断点的75%位于BCR着丝粒半区的两个支架相关区域（SAR）之间，而75%的t-AML患者断点位于一个强SAR内BCR的端粒半区。我们在BCR中绘制了其他结构元件。在三种白血病细胞系中，一个体内DNA拓扑II切割位点（由几种不同的靶向拓扑II的药物诱导）定位于外显子9附近。在四种白血病细胞系中，一个强DNase I超敏位点（HS）也定位于外显子9附近，其中包括两个MLL发生重排的细胞系[t(6;11)和t(9;11)]，以及两个MLL正常的淋巴母细胞系。其中两个白血病细胞系也显示出一个体内拓扑II切割位点。我们的结果表明，MLL BCR的染色质结构可能影响原发性和治疗相关性白血病中DNA断裂的位置。我们提出，拓扑II在MLL端粒SAR中富集，并且在用拓扑II抑制剂处理后，它会切割DNase I HS位点。这些事件可能参与与映射在MLL SAR中的t-AML/t-ALL断点相关的重组。
