Study on the mouse leukemia disease gene using the BXH-2 mouse and retrovirus.

利用BXH-2小鼠和逆转录病毒研究小鼠白血病疾病基因。

• 批准号: 11138258
• 负责人: NAKAMURA Takuro
• 金额: $ 6.4万
• 依托单位: Japanese Foundation For Cancer Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas (A)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11138258/
• 关键词: Evi9; BXH-2 mouse; myeloid leukemia; zinc finger protein; oncogene; transcriptional regulation; BCL6; differentiation

A novel myeloid leukemia gene, Evi9, has been isolated from the common retroviral integration site of BXH-2 mouse leukemia. The functional analysis of the Evi9 protein was carried out, and the human homologue of Evi9 was identified. The followings were clarified in this year.(l) The Evi9 gene encodes a zinc finger protein, and three protein isoforms are produced by alternative splicing. The isoforms that have a double zinc finger as well as an acidic domain are located in the nucleus, whereas the other isoform that lacks both domains are in the cytoplasm. It has been shown that Evi9 colocalizes with BCL6 in the nucleus, and we clarified that the double zinc finger of Evi9 and the POZ domain of BCL6 physically interact with each another.(2) The expression of Evi9 was downregulated during myeloid differentiation of the HL60 cell induced by retinoic acid. Moreover, induction of Evi9 blocked myeloid differentiation of the HL60 cell, and also it inhibited apoptosis during differentiation. On the other hand, when HL60 and U937 cells were differentiated toward the monocyte by TPA, Evi9 was transiently downregtulated and then it showed upregulated expression. We are currently investigating the role of Evi9 in monocytic differentiation.(3) Since it was suggested that the Evi9 protein functions as a transcriptional regtulator, the transcriptional activity of Evi9 was examined using GAL4 fusion proteins. Evi9 acts as the transcriptional repressor, and there is a repression domain in the zinc figer region.(4) The human EVI9 gene was shown to be located at chromosome 2p13 by FISH.As some cases of human malignant lymphoma have shown the abnormalites in this region, we are currently investigating the possible EVI9 involvement in malignant lymphoma.

从BXH-2小鼠白血病常见的逆转录病毒整合部位分离到一个新的髓系白血病基因Evi9。对Evi9蛋白进行了功能分析，并鉴定了Evi9的人类同源物。(L)Evi9基因编码一个锌指蛋白，通过选择性剪接产生三种蛋白质亚型。具有双锌指和酸性结构域的异构体位于细胞核中，而另一种没有两个结构域的异构体位于细胞质中。研究表明，Evi9与BCL6共定位于细胞核内，我们阐明了Evi9的双锌指与BCL6的POZ结构域之间存在物理上的相互作用。(2)在维甲酸诱导的HL60细胞髓系分化过程中，Evi9的表达下调。此外，Evi9的诱导抑制了HL60细胞的髓系分化，并抑制了分化过程中的细胞凋亡。另一方面，当TPA诱导HL60和U937细胞向单核细胞分化时，Evi9表达一过性下调，然后表达上调。我们目前正在研究Evi9在单核细胞分化中的作用。(3)由于Evi9蛋白被认为是一种转录调控因子，因此我们利用GAL4融合蛋白检测了Evi9的转录活性。(4)FISH发现人EVI9基因位于2p13号染色体上。由于一些人类恶性淋巴瘤病例显示该区域存在EVI9基因异常，我们目前正在研究EVI9基因与恶性淋巴瘤的关系。

项目成果

Nakamura T, Yamazaki Y, Hatano Y, Miura I.: "NUP98 is fused to PMX1 homeobox gene in human AML with chromosome translocation"Blood. 94(2). 741-747 (1999)

Nakamura T、Yamazaki Y、Hatano Y、Miura I.：“NUP98 在人类 AML 中与染色体易位的 PMX1 同源盒基因融合”Blood。

Hatano, Y., Miura, I., Nakamura, T., Yamazaki, Y., Takahashi, N.and Miura, A.B.: "Molecular heterogeneity of the NUP98/HOXA9 fusion transcript in myelodysplastic syndromes associated with t(7 ; 11)(p15 ; p15)."Br.J.Haematol.. 107. 600-604 (1999)

Hatano, Y.、Miura, I.、Nakamura, T.、Yamazaki, Y.、Takahashi, N. 和 Miura, A.B.：“与 t(7; 11) 相关的骨髓增生异常综合征中 NUP98/HOXA9 融合转录物的分子异质性