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

Randy Fenrick, Joseph M. Amann, Bart Lutterbach, Lilin Wang, Jennifer J. Westendorf, James R. Downing, Scott W. Hiebert

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6566-6574
Number of pages9
JournalMolecular and cellular biology
Volume19
Issue number10
DOIs
StatePublished - Oct 1999

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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