title: Mechanisms of transcriptional repression by the t(8;21)-, t(12;21)-, and inv(16)-encoded fusion proteins.
abstract: AML-1 is one of the most frequently translocated genes in human leukemia. AML-1 binds DNA and activates or represses transcription, while the chromosomal translocation fusion proteins in acute myeloid leukemia subvert these functions. The t(8;21) is the second most frequent translocation in acute myeloid leukemia and creates a fusion between the DNA binding domain of AML-1 and the ETO (also known as MTG8) corepressor. The t(12;21) is found in up to 25% of pediatric B cell acute lymphoblastic leukemias and fuses the ETS family transcription factor TEL to the amino terminus of AML-1. In addition, the inv(16), the most frequent translocation in acute myeloid leukemia, fuses the AML-1 cofactor CBFbeta to the smooth muscle myosin heavy chain MYH11. Both the t(8;21) and t(12;21) create transcriptional repressors that impair AML-1 target gene expression. We demonstrated that the fusion proteins encoded by these translocations contact the nuclear hormone corepressors (N-CoR/SMRT), mSin3A, and histone deacetylases. We have also found that both TEL and AML-1 interact with mSin3A. TEL also binds N-CoR and histone deacetylase-3, indicating that wild-type TEL is a transcriptional repressor. The t(12;21) fuses the mSin3A interaction domain of TEL to AML-1 to transform AML-1 from a regulated to an unregulated transcriptional repressor. The recognition that AML-1 interacts with mSin3A to repress transcription suggested that the inv(16) fusion protein might also repress the transcription of AML-1-target genes. In fact, the inv(16) encodes a protein that cooperates with AML-1 to repress transcription. The inv(16) fusion protein was found in a ternary complex with AML-1 and mSin3A, suggesting that the inv(16) also acts by recruiting transcriptional corepressors and histone deacetylases.
authors.affiliation: Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. scott.hiebert@mcmail.vanderbilt.edu
authors.forename: S W
authors.initials: SW
authors.lastname: Heibert
authors.forename: B
authors.initials: B
authors.lastname: Lutterbach
authors.forename: K
authors.initials: K
authors.lastname: Durst
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Linggi
authors.forename: S
authors.initials: S
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Wood
authors.forename: J
authors.initials: J
authors.lastname: Amann
authors.forename: D
authors.initials: D
authors.lastname: King
authors.forename: Y
authors.initials: Y
authors.lastname: Hou
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D007446:Chromosome Inversion; D002881:Chromosomes, Human, Pair 12; D002885:Chromosomes, Human, Pair 16; D002887:Chromosomes, Human, Pair 18; D002891:Chromosomes, Human, Pair 21; D050676:Core Binding Factor Alpha 2 Subunit; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins; D014157:Transcription Factors; C107844:AML1-ETO fusion protein, human; C095514:CBFbeta-MYH11 fusion protein; C539127:NCOR1 protein, human; C539128:Ncor1 protein, mouse; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein