title: The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription.
abstract: The t(12;21) translocation is present in up to 30% of childhood B-cell acute lymphoblastic and fuses a potential dimerization motif from the ets-related factor TEL to the N terminus of AML1. The t(12;21) translocation encodes a 93-kDa fusion protein that localizes to a high-salt- and detergent-resistant nuclear compartment. This protein binds the enhancer core motif, TGTGGT, and interacts with the AML-1-binding protein, core-binding factor beta. Although TEL/AML-1B retains the C-terminal domain of AML-1B that is required for transactivation of the T-cell receptor beta enhancer, it fails to activate transcription but rather inhibits the basal activity of this enhancer. TEL/AML-1B efficiently interferes with AML-1B dependent transactivation of the T-cell receptor beta enhancer, and coexpression of wild-type TEL does not reverse this inhibition. The N-terminal TEL helix-loop-helix domain is essential for TEL/AML-1B-mediated repression. Thus, the t(12;21) fusion protein dominantly interferes with AML-1B-dependent transcription, suggesting that the inhibition of expression of AML-1 genes is critical for B-cell leukemogenesis.
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Hiebert
authors.forename: W
authors.initials: W
authors.lastname: Sun
authors.forename: J N
authors.initials: JN
authors.lastname: Davis
authors.forename: T
authors.initials: T
authors.lastname: Golub
authors.forename: S
authors.initials: S
authors.lastname: Shurtleff
authors.forename: A
authors.initials: A
authors.lastname: Buijs
authors.forename: J R
authors.initials: JR
authors.lastname: Downing
authors.forename: G
authors.initials: G
authors.lastname: Grosveld
authors.forename: M F
authors.initials: MF
authors.lastname: Roussell
authors.forename: D G
authors.initials: DG
authors.lastname: Gilliland
authors.forename: N
authors.initials: N
authors.lastname: Lenny
authors.forename: S
authors.initials: S
authors.lastname: Meyers
mesh_terms: D001483:Base Sequence; D002881:Chromosomes, Human, Pair 12; D002891:Chromosomes, Human, Pair 21; D004268:DNA-Binding Proteins / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008969:Molecular Sequence Data; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012097:Repressor Proteins; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D004268:DNA-Binding Proteins; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000097764:ETS Translocation Variant 6 Protein