Department of Biopathology, University of 'Rome Tor Vergata', Rome, Italy.
Genes Chromosomes Cancer. 2010 Aug;49(8):726-32. doi: 10.1002/gcc.20783.
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, approximately 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.
我们比较了 23 例治疗相关性急性早幼粒细胞白血病（t-APL）和 25 例初发 APL 患者 PML 和 RARA 基因座的基因组断裂点。18 例 t-APL 患者因原发性疾病接受拓扑异构酶 II 毒物米托蒽醌治疗。在接触该药物的患者中，39%的 t-APL 发生了 8bp“热点”区域的 PML 断裂，而初发 APL 患者中无一例发生（P=0.007）。至于 RARA 断裂点，在接受该药物治疗的患者中，65%的 t-APL 和 28%的初发 APL 患者分别在 2 号内含子的 3'区域（区域 B）发生聚类。扫描统计显示，t-APL 病例中 RARA 断裂点在区域 B 明显聚类（P=0.001），而初发 APL 则无（P=1）。此外，RARA 区域 B 下游约 300bp 处含有与拓扑异构酶 II 一致序列高度同源的序列。PML 和 RARA 基因座的 DNA 断裂点的偏态分布表明，t-APL 与初发 APL 相比存在不同的发病机制。
