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

Mol Cell Biol. 1999 Oct;19(10):6566-74. doi: 10.1128/MCB.19.10.6566.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Burkitt Lymphoma / genetics
  • Child
  • Chromosomes, Human, Pair 12
  • Chromosomes, Human, Pair 21
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • ETS Translocation Variant 6 Protein
  • Humans
  • Models, Genetic
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-ets
  • Proto-Oncogene Proteins*
  • RUNX1 Translocation Partner 1 Protein
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Sin3 Histone Deacetylase and Corepressor Complex
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Translocation, Genetic*

Substances

  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • RUNX1 Translocation Partner 1 Protein
  • RUNX1 protein, human
  • RUNX1T1 protein, human
  • Repressor Proteins
  • SIN3A transcription factor
  • TEL-AML1 fusion protein
  • Transcription Factors
  • Sin3 Histone Deacetylase and Corepressor Complex