Reiter Andreas, Saussele Susanne, Grimwade David, Wiemels Joseph L, Segal Mark R, Lafage-Pochitaloff Marina, Walz Christoph, Weisser Andreas, Hochhaus Andreas, Willer Andreas, Reichert Anja, Büchner Thomas, Lengfelder Eva, Hehlmann Rüdiger, Cross Nicholas C P
III. Medizinische Universitätsklinik, Klinikum Mannheim, Fakultät für Klinische Medizin der Universität Heidelberg, Germany.
Genes Chromosomes Cancer. 2003 Feb;36(2):175-88. doi: 10.1002/gcc.10154.
The genomic breakpoints in the t(15;17)(q22;q21), associated with acute promyelocytic leukemia (APL), are known to occur within three different PML breakpoint cluster regions (bcr) on chromosome 15 and within RARA intron 2 on chromosome 17; however, the precise mechanism by which this translocation arises is unclear. To clarify this mechanism, we (i). assembled the sequence of RARA intron 2, (ii). amplified and sequenced the genomic PML-RARA junction sequences from 37 APL patients, and (iii). amplified and sequenced the reverse RARA-PML genomic fusion in 29 of these cases. Three significant breakpoint microclusters within RARA intron 2 were identified, suggesting that sequence-associated or structural factors play a role in the formation of the t(15;17). There was no evidence that the location of a breakpoint in PML had any relationship to the location of the corresponding breakpoint in RARA. Although some sequence motifs previously implicated in illegitimate recombinations were found in the microcluster regions, these associations were not significant. Comparison of forward and reverse genomic junctions revealed microhomologies, deletions, and/or duplications of either gene in all but one case, in which a complex rearrangement with inversion of the PML-derived sequence was found. These findings are consistent with the hypothesis that the t(15;17) occurs by nonhomologous recombination of DNA after processing of the double-strand breaks by a dysfunctional DNA damage-repair mechanism.
与急性早幼粒细胞白血病（APL）相关的t(15;17)(q22;q21)基因组断点，已知发生在15号染色体上的三个不同的早幼粒细胞白血病断点簇区域（bcr）内以及17号染色体上的维甲酸受体α（RARA）内含子2内；然而，这种易位产生的确切机制尚不清楚。为了阐明这一机制，我们（i）. 组装了RARA内含子2的序列，（ii）. 扩增并测序了37例APL患者的基因组早幼粒细胞白血病-维甲酸受体α（PML-RARA）连接序列，以及（iii）. 在其中29例病例中扩增并测序了反向的维甲酸受体α-早幼粒细胞白血病（RARA-PML）基因组融合序列。在RARA内含子2内鉴定出三个显著的断点微簇，表明序列相关或结构因素在t(15;17)的形成中起作用。没有证据表明早幼粒细胞白血病（PML）中断点的位置与维甲酸受体α（RARA）中相应断点的位置有任何关系。虽然在微簇区域发现了一些先前与异常重组有关的序列基序，但这些关联并不显著。正向和反向基因组连接的比较揭示了除一例以外的所有病例中两个基因的微同源性、缺失和/或重复，在该例中发现了早幼粒细胞白血病（PML）衍生序列倒位的复杂重排。这些发现与以下假设一致，即t(15;17)是由功能失调的DNA损伤修复机制处理双链断裂后DNA的非同源重组发生的。
