Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia
Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia
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DOI：
10.1038/onc.2009.475
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发表时间：
2010-04-01
期刊：
影响因子：
8
通讯作者：
Honda, H.
中科院分区：
文献类型：
--
作者：
Yamasaki, N.;Miyazaki, K.;Honda, H.
E2a-肝白血病因子(HLF)是一种嵌合蛋白，发现有t(17；19)的B系急性淋巴细胞白血病(ALL)。为了分析白血病的发生过程并建立t(17；19)阳性白血病的模型小鼠，我们为E2A-HLF建立了可诱导敲入(Iki)小鼠。尽管E2A-HLF在造血组织中被诱导表达，但在长期的观察期内没有发生疾病，这表明白血病的发生需要额外的基因改变。为了阐明这一过程，对E2A-HLF Iki和对照仔猪进行了逆转录病毒插入突变。病毒感染可导致E2a-HLF Iki小鼠发生急性白血病，其发病率和死亡率均高于对照组。反向聚合酶链式反应检测到三个常见的针对E2A-HLF Iki白血病小鼠的整合位点，它们诱导锌指转录因子的过度表达：生长因子独立1(Gfi1)、锌指蛋白亚家族1A1亚家族a(Zfp1a1，也称为Ikaros)和锌指蛋白521(Zfp521)。有趣的是，Zfp521整合的肿瘤只表现为B系ALL，这与人类t(17；19)阳性白血病的表型相对应。此外，ZNF521(人类Zfp521的等价物)在含有t(17；19)的人白血病细胞系中过表达。此外，E2A-HLF的Iki和Zfp521转基因小鼠的Iki都经常发生B系ALL。这些结果表明，一组转录因子促进了表达E2A-HLF的造血祖细胞的白血病转化，提示Zfp521/ZNF521的异常表达可能与t(17；19)阳性B系ALL有关。Oncogene(2010年)29,1963年-1975年；doi：10.1038/onc.2009.475；2010年1月11日在线发布
E2A-hepatic leukemia factor (HLF) is a chimeric protein found B-lineage acute lymphoblastic leukemia (ALL) with t(17;19). To analyze the leukemogenic process and to create model mice for t(17;19)-positive leukemia, we generated inducible knock-in (iKI) mice for E2A-HLF. Despite the induced expression of E2A-HLF in the hematopoietic tissues, no disease was developed during the long observation period, indicating that additional gene alterations are required to develop leukemia. To elucidate this process, E2A-HLF iKI and control littermates were subjected to retroviral insertional mutagenesis. Virus infection induced acute leukemias in E2A-HLF iKI mice with higher morbidity and mortality than in control mice. Inverse PCR detected three common integration sites specific for E2A-HLF iKI leukemic mice, which induced overexpression of zinc-finger transcription factors: growth factor independent 1 (Gfi1), zinc-finger protein subfamily 1A1 isoform a (Zfp1a1, also known as Ikaros) and zinc-finger protein 521 (Zfp521). Interestingly, tumors with Zfp521 integration exclusively showed B-lineage ALL, which corresponds to the phenotype of human t(17;19)-positive leukemia. In addition, ZNF521 (human counterpart of Zfp521) was found to be over-expressed in human leukemic cell lines harboring t(17;19). Moreover, both iKI for E2A-HLF and transgenic for Zfp521 mice frequently developed B-lineage ALL. These results indicate that a set of transcription factors promote leukemic transformation of E2A-HLF-expressing hematopoietic progenitors and suggest that aberrant expression of Zfp521/ZNF521 may be clinically relevant to t(17;19)positive B-lineage ALL. Oncogene (2010) 29, 1963-1975; doi:10.1038/onc.2009.475; published online 11 January 2010