TEL-AML1融合転写調節因子の発癌機序の分析

为了阐明从儿童白血病中分离的白血病嵌合转录因子TEL-AML1的机制，我们分析了造血细胞凋亡的调控系统。由于以前的研究表明RAS通路的激活与该系统有关，而且最近的研究发现线粒体外膜上的特定的Bcl2超家族成员通过调节细胞色素c从线粒体到胞浆的转位而发挥关键作用来控制细胞的存活，我们推测RAS通路下游调控的Bcl2家族成员是决定造血祖细胞命运的关键因素。我们发现该家族中的两个成员：Bclxl和Bim受细胞因子的调节，而前者不受活性RAS的影响。后者是BH3中唯一含有细胞死亡激活因子的成员，与BH2超家族中的抗凋亡亚家族成员结合并下调其功能，在其mRNA水平上通过激活RAS通路而下调，因此被认为是预测的控制造血细胞存活的关键因素。在我们测试的白血病细胞中，BIM的表达下调，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。

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.