Identification of cooperative genes for E2A-PBX1 to develop acute lymphoblastic leukemia.
Identification of cooperative genes for E2A-PBX1 to develop acute lymphoblastic leukemia.
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DOI：
10.1111/cas.12945
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发表时间：
2016-07
期刊：
影响因子：
5.7
通讯作者：
Honda H
中科院分区：
文献类型：
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作者：
Sera Y;Yamasaki N;Oda H;Nagamachi A;Wolff L;Inukai T;Inaba T;Honda H
E2 A-PBX 1是在具有B-细胞谱系的携带t（1;19）的急性淋巴细胞白血病（ALL）中检测到的嵌合基因产物。为了研究白血病发生过程，我们产生了E2 A-PBX 1的条件性敲入（cKI）小鼠，其中E2 A-PBX 1在内源性E2 A启动子的控制下诱导表达。尽管E2 A-PBX 1的诱导表达，但没有观察到造血系统疾病，这强烈表明需要额外的遗传改变来发展白血病。为了解决这种可能性，使用逆转录病毒插入诱变。病毒感染可有效诱导E2 A-PBX 1 cKI小鼠的T细胞、B细胞和双表型ALL。反向PCR确定了8个逆转录病毒的共同整合位点，其中Gfi 1，Mycn和Pim 1基因的表达增强。此外，值得注意的是，在一个B细胞系肿瘤中检测到Zfp 521基因的病毒整合和过表达;我们先前将Zfp 521鉴定为与E2 A-HLF的协同基因，E2 A-HLF是另一个与B-系ALL融合的E2 A-基因。E2 A-PBX 1 cKI，Zfp 521转基因复合小鼠发生B-系ALL的发现表明E2 A-PBX 1与过表达的Zfp 521在B-细胞肿瘤发生中的协同致癌性。此外，在几个携带t（1;19）的人白血病细胞系中发现了Zfp 521的人类对应物ZNF 521的上调。这些结果表明，E2 A-PBX 1与其他基因改变合作发展ALL。其中，ZNF 521的表达增强可能在E2 A融合基因发生B系ALL中发挥临床相关作用。
E2A‐PBX1 is a chimeric gene product detected in t(1;19)‐bearing acute lymphoblastic leukemia (ALL) with B‐cell lineage. To investigate the leukemogenic process, we generated conditional knock‐in (cKI) mice for E2A‐PBX1, in which E2A‐PBX1 is inducibly expressed under the control of the endogenous E2A promoter. Despite the induced expression of E2A‐PBX1, no hematopoietic disease was observed, strongly suggesting that additional genetic alterations are required to develop leukemia. To address this possibility, retroviral insertional mutagenesis was used. Virus infection efficiently induced T‐cell, B‐cell, and biphenotypic ALL in E2A‐PBX1 cKI mice. Inverse PCR identified eight retroviral common integration sites, in which enhanced expression was observed in the Gfi1, Mycn, and Pim1 genes. In addition, it is of note that viral integration and overexpression of the Zfp521 gene was detected in one tumor with B‐cell lineage; we previously identified Zfp521 as a cooperative gene with E2A‐HLF, another E2A‐involving fusion gene with B‐lineage ALL. The cooperative oncogenicity of E2A‐PBX1 with overexpressed Zfp521 in B‐cell tumorigenesis was indicated by the finding that E2A‐PBX1 cKI, Zfp521 transgenic compound mice developed B‐lineage ALL. Moreover, upregulation of ZNF521, the human counterpart of Zfp521, was found in several human leukemic cell lines bearing t(1;19). These results indicate that E2A‐PBX1 cooperates with additional gene alterations to develop ALL. Among them, enhanced expression of ZNF521 may play a clinically relevant role in E2A fusion genes to develop B‐lineage ALL.