Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein.

Fenrick R, Amann JM, Lutterbach B, Wang L, Westendorf JJ, Downing JR, Hiebert SW
Mol Cell Biol. 1999 19 (10): 6566-74

PMID: 10490596 · PMCID: PMC84626 · DOI:10.1128/mcb.19.10.6566

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.

MeSH Terms (18)

Burkitt Lymphoma Child Chromosomes, Human, Pair 12 Chromosomes, Human, Pair 21 Core Binding Factor Alpha 2 Subunit DNA-Binding Proteins Humans Models, Genetic Neoplasm Proteins Oncogene Proteins, Fusion Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins Proto-Oncogene Proteins c-ets Repressor Proteins RUNX1 Translocation Partner 1 Protein Transcription Factors Translocation, Genetic

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