Enhanced expression of p210BCR/ABL and aberrant expression of Zfp423/ZNF423 induce blast crisis of chronic myelogenous leukemia
Enhanced expression of p210BCR/ABL and aberrant expression of Zfp423/ZNF423 induce blast crisis of chronic myelogenous leukemia
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DOI：
10.1182/blood-2007-05-088724
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发表时间：
2009-05-07
期刊：
影响因子：
20.3
通讯作者：
Honda, Hiroaki
中科院分区：
文献类型：
--
作者：
Miyazaki, Kazuko;Yamasaki, Norimasa;Honda, Hiroaki
慢性粒细胞白血病（CML）是一种起源于p210 BCR/ABL转化的干细胞的造血系统疾病，其开始为惰性慢性期（CP），但进展为致命的急变期（BC）。为了研究疾病演变的分子机制，将CML表现的p210 BCR/ABL转基因小鼠与传播可复制逆转录病毒的BXH 2小鼠杂交。BXH 2背景的非转基因小鼠仅发生急性髓性白血病，而p210 BCR/ABL转基因同窝小鼠发生非髓性白血病，其中反向聚合酶链反应检测到2个常见的病毒整合位点（CIS）。有趣的是，一个CIS是转基因自身的启动子，其上调p210 BCR/ABL表达。另一个是转录因子Zfp 423的5'非编码区，其诱导Zfp 423的异常表达。Zfp 423和p210 BCR/ABL的协同活性证明如下：（1）在p210 BCR/ABL转基因骨髓（BM）细胞中引入Zfp 423增加了集落形成能力，（2）ZNF 423抑制了p210 BCR/ABL转基因骨髓（BM）细胞的集落形成能力，（3）ZNF 423抑制了p210 BCR/ABL转基因骨髓（BM）细胞的集落形成能力。（Zfp 423的人同源物）在表达ZNF 423的p210 BCR/ABL阳性造血细胞中抑制细胞生长，（3）接受Zfp 423和p210 BCR/ABL转导的BM细胞移植的小鼠发生急性白血病;（4）在人BCR/ABL阳性细胞系和CML BC样品中发现ZNF 423的表达。这些结果表明，p210 BCR/ABL的表达增强和Zfp 423/ZNF 423的表达失调有助于CML BC。（血。2009;113：4702-4710）
Chronic myelogenous leukemia (CML) is a hematopoietic disorder originating from p210BCR/ABL-transformed stem cells, which begins as indolent chronic phase (CP) but progresses into fatal blast crisis (BC). To investigate molecular mechanism(s) underlying disease evolution, CML-exhibiting p210BCR/ABL transgenic mice were crossed with BXH2 mice that transmit a replication-competent retrovirus. Whereas nontransgenic mice in the BXH2 background exclusively developed acute myeloid leukemia, p210BCR/ABL transgenic littermates developed nonmyeloid leukemias, in which inverse polymerase chain reaction detected 2 common viral integration sites (CISs). Interestingly, one CIS was transgene's own promoter, which up-regulated p210BCR/ABL expression. The other was the 5' noncoding region of a transcription factor, Zfp423, which induced aberrant Zfp423 expression. The cooperative activities of Zfp423 and p210BCR/ABL were demonstrated as follows: (1) introduction of Zfp423 in p210BCR/ABL transgenic bone marrow ( BM) cells increased colony-forming ability, (2) suppression of ZNF423 (human homo-logue of Zfp423) in ZNF423-expressing, p210BCR/ABL-positive hematopoietic cells retarded cell growth, (3) mice that received a transplant of BM cells transduced with Zfp423 and p210BCR/ABL developed acute leukemia, and (4) expression of ZNF423 was found in human BCR/ABL-positive cell lines and CML BC samples. These results demonstrate that enhanced expression of p210BCR/ABL and deregulated expression of Zfp423/ZNF423 contribute to CML BC. (Blood. 2009;113:4702-4710)