Naoe T, Kudo K, Yoshida H, Horibe K, Ohno R
Department of Medicine, Nagoya University Branch Hospital, Japan.
Leukemia. 1997 Apr;11 Suppl 3:287-8.
To study mechanism of chromosomal translocation, we analyzed the breakpoints (b/p) of the PML and RARA genes in 120 and 5 patients with de novo and secondary (therapy-related) acute promyelocytic leukemia (APL), respectively. In de novo APL, the b/p in the PML gene were clustered in introns 3 (bcr 3; 30%) and around intron 6 (bcr 1 and 2: 70%). The b/p of the RARA gene were widely distributed in intron 2. In studied 8 de novo APL patients, no consensus sequence-motif was found around the b/p, but there were identical stretches of one to seven nucleotides between the PML and RARA genes in the joining regions, suggesting non-selective DNA double strand cleavage followed by single strand base-pairing within identical short stretches as a molecular mechanism of the translocation. In 4 secondary APL patients after chemotherapy including etoposide against Langerhans cell histiocytosis, the b/p of the PML gene were located in intron 6, and those of the RARA gene were in a restricted region within intron 2, 1 kb EcoRI-BamHI fragment, while in an APL patient after chemotherapy without etoposide against breast cancer, the b/p of the PML and RARA genes were located in intron 6 and another region within intron 2, respectively. These data suggest that a different mechanism was associated with the t(15;17) translocation in etoposide-related APL.
为研究染色体易位的机制，我们分别分析了120例初发和5例继发（治疗相关）急性早幼粒细胞白血病（APL）患者中PML和RARA基因的断点（b/p）。在初发APL中，PML基因的断点集中在内含子3（bcr 3；30%）和内含子6周围（bcr 1和2：70%）。RARA基因的断点广泛分布在内含子2中。在所研究的8例初发APL患者中，在断点周围未发现共有序列基序，但在连接区域的PML和RARA基因之间存在1至7个核苷酸的相同片段，提示非选择性DNA双链断裂后在相同短片段内进行单链碱基配对是易位的分子机制。在4例接受包括依托泊苷治疗朗格汉斯细胞组织细胞增多症后的继发APL患者中，PML基因的断点位于内含子6，RARA基因的断点位于内含子2内一个受限区域，即1 kb EcoRI - BamHI片段，而在1例未接受依托泊苷治疗乳腺癌后的APL患者中，PML和RARA基因的断点分别位于内含子6和内含子2内的另一个区域。这些数据表明，在依托泊苷相关的APL中，t(15;17)易位存在不同的机制。
