Specific protein redirection as a transcriptional therapy approach for t(8;21) leukemia
2003
Leukemias are often characterized by specific balanced translocations (1). Most of the chromosomal translocations in acute myeloid leukemia (AML) result in chimeric proteins involving transcription factors, often fusing a DNA-binding domain of a transcriptional activator to a transcriptional repressor. Thus, the transcriptional repressor is dislocated to target genes of the transcriptional activator, which are thought to play an important role in the differentiation process of hematopoietic cells.
The most frequent chromosomal translocation in AML is the t(8;21) translocation, found in 10–15% of adult patients with this disease (2). Due to this translocation, the C terminus of the transcriptional activator AML1 is replaced by the transcriptional repressor ETO and results in the fusion protein AML1-ETO (3, 4). ETO recruits corepressors and histone deacetylases (HDACs), and by this mechanism AML1-ETO represses AML1 target genes. This mechanism is thought to be responsible for the differentiation block that is characteristic of AML. In addition, we have recently shown that AML1-ETO inhibits expression of the p14ARF tumor suppressor (5). AML1-ETO also interacts with various transcription factors including myeloid elf-like factor (MEF), CCAAT/enhancer binding protein A (C/EBPA), other E26-transformation-specific (ETS) family members, and activating-protein 1 (AP-1). In fact it is the physical interaction between AML1-ETO and C/EBPA that is thought to be responsible for the repression of C/EBPA expression, which may contribute to the block in differentiation (6–9).
The goal of our study was to analyze whether redirection of an oncogenic transcriptional repressor protein could be used to specifically induce cell death in malignant cells. We chose t(8;21)-positive leukemia as an example. Here, we show evidence that AML1-ETO can be targeted to a different set of promoters by using a specifically designed chimeric protein. This redirection induced rapid cell death in AML1-ETO-expressing cells. Importantly, no adverse effects were noted for AML1-ETO-negative cells.
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