Abstract：
A major unresolved question for 11q23 translocations involving MLL is the chromosomal mechanism(s) leading to these translocations. We have mapped breakpoints within the 8.3-kb BamHI breakpoint cluster region in 31 patients with acute lymphoblastic leukemia and acute myeloid leukemia (AML) de novo and in 8 t-AML patients. In 23 of 31 leukemia de novo patients, MLL breakpoints mapped to the centromeric half (4.57 kb) of the breakpoint cluster region, whereas those in eight de novo patients mapped to the telomeric half (3.87 kb). In contrast, only two t-AML breakpoints mapped in the centromeric half, whereas six mapped in the telomeric half. The difference in distribution of the leukemia de novo breakpoints is statistically significant (P = .02). A similar difference in distribution of breakpoints between de novo patients and t-AML patients has been reported by others. We identified a low- or weak-affinity scaffold attachment region (SAR) mapping just centromeric to the breakpoint cluster region, and a high-affinity SAR mapping within the telomeric half of the breakpoint cluster region. Using high stringency criteria to define in vitro vertebrate topoisomerase II (topo II) consensus sites, one topo II site mapped adjacent to the telomeric SAR, whereas six mapped within the SAR. Therefore, 74% of leukemia de novo and 25% of t-AML breakpoints map to the centromeric half of the breakpoint cluster region map between the two SARs; in contrast, 26% of the leukemia de novo and 75% of the t-AML patient breakpoints map to the telomeric half of the breakpoint cluster region that contains both the telomeric SAR and the topo II sites. Thus, the chromatin structure of the MLL breakpoint cluster region may be important in determining the distribution of the breakpoints. The data suggest that the mechanism(s) leading to translocations may differ in leukemia de novo and in t-AML.
摘要：
涉及MLL的11q23易位的主要未解决的问题是导致这些易位的染色体机制。我们已经在31例急性淋巴细胞白血病和急性髓细胞性白血病（AML）患者和8例t-AML患者的8.3kbBamHI断点簇区域内绘制了断点。在31名初发白血病患者中，有23名，MLL断点映射到断点簇区域的着丝粒一半（4.57kb），而8名新生患者中的那些映射到端粒一半（3.87kb）。相比之下,只有两个t-AML断点映射在着丝粒的一半，而六个映射在端粒的一半。白血病从头断点的分布差异具有统计学意义(P=.02)。其他人已经报道了从头患者和t-AML患者之间断点分布的类似差异。我们确定了一个低亲和力或弱亲和力的支架附着区（SAR）映射只是着丝粒到断点簇区域，以及断点簇区域的端粒一半内的高亲和力SAR映射。使用高严格性标准来定义体外脊椎动物拓扑异构酶II（topoII）共有位点，一个与端粒SAR相邻的topoII位点，而六个映射在SAR内。因此,74％的白血病从头和25％的t-AML断点映射到两个SAR之间的断点簇区域图的着丝粒一半；相反，从头26％的白血病和75％的t-AML患者断点映射到包含端粒SAR和topoII位点的断点簇区域的端粒一半。因此，MLL断点簇区域的染色质结构在确定断点的分布中可能是重要的。数据表明，导致易位的机制可能在从头白血病和t-AML中有所不同。
