TEL-AML1融合転写調節因子の発癌機序の分析

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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.