TEL-AML1融合転写調節因子の発癌機序の分析

TEL-AML1融合转录调节因子致癌机制分析

• 批准号: 10670965
• 负责人: INABA Toshiya
• 金额: $ 2.05万
• 依托单位: Jichi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670965/
• 关键词: apoptosis; leukemia; chimera; TEL-AML1; E2A-HLF; BH3 factor; Bim; cytokine; E2A-HLK; キメラ転写因子; ALL; レトロウイルス

In order to elucidate mechanisms, through which leukemogenic chimeric transcription factors isolated from childhood leukemia such as TEL-AMLl, we analyzed regulation system of apoptosis in hematopoietic cells. Because previous studies indicated that the activation of Ras pathways is implicated in this system, and because recent studies revealed that specific members of the Bcl-2 superfamily on the outer membrane of mitochondria plays critical roles to control cell survival through regulating the translocation of cytochrome c from mitochondria to cytosol, we assumed that Bcl-2 family members that are regulated downstream of Ras pathways are the key factors to determine the fate of hematopoietic progenitors. We found that two members of this family, Bcl-xL and Bim, are regulated by cytokines, however the former is not affected by active Ras. The latter, a member of the BH3-only containing cell death activator, which binds to members of the antiapoptotic subfamily in the Bcl-2 superfamily and downregulates their function, is downregulated through activating Ras pathways in its mRNA levels, thus is considered to be the predicted key factors to control cell survival of hematopoietic cells. Bim expression is downregulated in leukemia cells we tested, especially those expressing the Bcr-Abl chimeric tyrosine kinase. We are currently investigating possible roles of leukemogenic chimeras in the regulation system of Bim expression.

为了阐明从儿童白血病中分离出致白血病嵌合转录因子如TEL-AML1的机制，我们分析了造血细胞凋亡的调控系统。因为以前的研究表明Ras通路的激活与该系统有关，并且因为最近的研究表明线粒体外膜上的Bcl-2超家族的特定成员通过调节细胞色素c从线粒体到胞质溶胶的移位来控制细胞存活，我们假设在Ras通路下游受调节的Bcl-2家族成员是决定造血祖细胞命运的关键因素。我们发现这个家族的两个成员Bcl-xL和Bim受细胞因子的调节，而前者不受活性Ras的影响。后者是仅含BH 3的细胞死亡激活剂的成员，其结合Bcl-2超家族中的抗凋亡亚家族成员并下调其功能，通过在其mRNA水平上激活Ras途径而下调，因此被认为是控制造血细胞的细胞存活的预测关键因素。Bim的表达在我们检测的白血病细胞中下调，特别是那些表达Bcr-Abl嵌合酪氨酸激酶的细胞。我们目前正在研究白血病嵌合体在Bim表达调控系统中的可能作用。

项目成果

Honda et al.: "Expression of E2A-HLF chimeric ・・・"Blood. 93. 2780-2790 (1999)

Honda 等人：“E2A-HLF 嵌合体的表达……”血液。 93. 2780-2790 (1999)

Inukai et al: "The ADI and AD2 transactivation"Mol. Cell. Biology. 18. 6035-6043 (1998)

Inukai 等人：“ADI 和 AD2 反式激活”Mol。

Kurosawa et al: "Two candidate downstream target . . ."Blood. 93. 321-332 (1999)

黑泽等人：“两个候选下游目标……”血。

.Inukai T., Inaba T., Ikushima S., Look A.T: "The AD1 and AD2 transactivation domains of E2A are essential for the antiapoptotic activity of the E2A-HLF chimeric oncoprotein."Mol. Cell. Biol.. 18. 6035-6043 (1998)

Inukai T.、Inaba T.、Ikushima S.、Look A.T：“E2A 的 AD1 和 AD2 反式激活结构域对于 E2A-HLF 嵌合癌蛋白的抗凋亡活性至关重要。”

Hitzler et al.: "Expression patterns of the hepatic ・・・"Brain Res. 820. 1-11 (1999)

Hitzler 等人：“肝脏的表达模式......”Brain Res。 820. 1-11 (1999)