Both TEL and AML-1 Contribute Repression Domains to the t(12;21) Fusion Protein

Abstract

t(12;21) is the most frequent translocation found in pediatric B-cell acute lymphoblastic leukemias. This translocation fuses a putative repressor domain from the TEL DNA-binding protein to nearly all of the AML-1B transcription factor. Here, we demonstrate that fusion of the TEL pointed domain to the GAL4 DNA-binding domain resulted in sequence-specific transcriptional repression, indicating that the pointed domain is a portable repression motif. The TEL pointed domain functioned equally well when the GAL4 DNA-binding sites were moved 600 bp from the promoter, suggesting an active mechanism of repression. This lead us to demonstrate that wild-type TEL and the t(12;21) fusion protein bind the mSin3A corepressor. In the fusion protein, both TEL and AML-1B contribute mSin3 interaction domains. Deletion mutagenesis indicated that both the TEL and AML-1B mSin3-binding domains contribute to repression by the fusion protein. While both TEL and AML-1B associate with mSin3A, TEL/AML-1B appears to bind this corepressor much more stably than either wild-type protein, suggesting a mode of action for the t(12;21) fusion protein.

TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL

“…Interestingly, the inhibition is similar to that observed when overexpressing AML1. Previous studies have shown that the HLH domain is required for the transcriptional repression of AML1-dependent promoters by TEL-AML1 Fears et al, 1997;Fenrick et al, 1999;Uchida et al, 1999). TEL-AML1 lacking a HLH domain activates AML1-dependent transcription, albeit not as effectively as AML1.…”

“…To determine which domains are required for TEL-AML1 activity in vitro and in vivo, we generated a number of deletion mutants based on previous studies (Fenrick et al, 1999;Uchida et al, 1999;Guidez et al, 2000) (Figure 1). These studies found that deletion of the runt homology domain (RHD) domain abolished TEL-AML1 binding to AML1 consensus sequences, whereas deletions of the C-terminal transactivation domain of AML1 or the HLH domain of TEL did not affect the ability of TEL-AML1 to bind to DNA (Uchida et al, 1999).…”

“…TEL-AML1 is a chimeric transcription factor that can bind AML1 target sequences and potentially deregulate gene expression in cells harboring the translocation. TEL-AML1 has been shown to inhibit AML1-dependent transcription of several promoters in transient transfection assays and functional domains of both TEL and AML1 are required for this activity Fears et al, 1997;Fenrick et al, 1999;Uchida et al, 1999). These studies suggested that the TEL moiety of the fusion converts AML1 from an activator to a repressor of transcription.…”

Dual function of the epithelial specific ets transcription factor, ELF3, in modulating differentiation

“…It has been demonstrated that another ets factor, TEL, can act as a transcriptional repressor, in part through interaction with a co-repressor through its pointed domain (Fenrick et al, 1999).…”

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

“…The other class of TEL's partner genes encodes transcription factors such as RUNX1/AML1, which codes for a DNA binding subunit of the core binding factor (CBF; Speck, 2001). The TEL-AML1 fusion protein oligomerizes and exhibits repressive transcription properties and dominant-negative effect on normal AML1 activity (Hiebert et al, 1996;Fenrick et al, 1999). We recently described a TEL-ARNT fusion protein in a case of human acute myeloblastic leukemia (AML; Salomon-Nguyen et al, 2000).…”