Analysis of t(15;17) Chromosomal Breakpoint Sequences in Therapy-Related Versus De Novo Acute Promyelocytic Leukemia: Association of DNA Breaks with Specific DNA Motifs at PML and RARA Loci
Analysis of t(15;17) Chromosomal Breakpoint Sequences in Therapy-Related Versus De Novo Acute Promyelocytic Leukemia: Association of DNA Breaks with Specific DNA Motifs at PML and RARA Loci
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DOI：
10.1002/gcc.20783
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发表时间：
2010-08-01
影响因子：
3.7
通讯作者：
Lo-Coco, Francesco
中科院分区：
文献类型：
--
作者：
Hasan, Syed Khizer;Ottone, Tiziana;Lo-Coco, Francesco
我们比较了23例治疗相关急性早幼粒细胞白血病（t-APL）和25例新发APL患者的PML和RARA基因座的基因组断点。23例t-APL患者中18例接受拓扑异构酶Ⅱ毒物米托蒽醌治疗。DNA断裂聚集在一个先前报道的8 bp的“热点”区域的PML对应的一个首选网站的米托蒽醌诱导的DNA拓扑异构酶II介导的切割在39%的t-APL发生在患者暴露于这种代理，并在没有从头出现的情况下（P = 0.007）。RARA断裂点聚集在内含子2的3'区（B区）的发生率分别为65%和28%。扫描统计显示，与原发性APL（P = 1）相比，t-APL病例（P = 0.001）中RARA断点在区域B中显著聚集。此外，类似于RARA区域B下游300 bp包含与拓扑异构酶II共有序列高度同源的序列。PML和RARA基因的DNA断裂点的偏性分布提示t-APL的发病机制与原发APL不同。(C)2010 Wiley-Liss，Inc.
We compared genomic breakpoints at the PML and RARA loci in 23 patients with therapy-related acute promyelocytic leukemia (t-APL) and 25 de novo APL cases. Eighteen of 23 t-APL cases received the topoisomerase II poison mitoxantrone for their primary disorder. DNA breaks were clustered in a previously reported 8 bp "hot spot" region of PML corresponding to a preferred site of mitoxantrone-induced DNA topoisomerase II-mediated cleavage in 39% of t-APL occurring in patients exposed to this agent and in none of the cases arising de novo (P = 0.007). As to RARA breakpoints, clustering in a 3' region of intron 2 (region B) was found in 65% of t-APL and 28% of de novo APL patients, respectively. Scan statistics revealed significant clustering of RARA breakpoints in region B in t-APL cases (P = 0.001) as compared to de novo APL (P = 1). Furthermore, similar to 300 bp downstream of RARA region B contained a sequence highly homologous to a topoisomerase II consensus sequence. Biased distribution of DNA breakpoints at both PML and RARA loci suggest the existence of different pathogenetic mechanisms in t-APL as compared with de novo APL. (C) 2010 Wiley-Liss, Inc.