The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription

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Mol. Cell. Biol., Apr 1996, 1349-1355, Vol 16, No. 4
Copyright © 1996, American Society for Microbiology

The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription

SW Hiebert, W Sun, JN Davis, T Golub, S Shurtleff, A Buijs, JR Downing, G Grosveld, MF Roussell, DG Gilliland, N Lenny and S Meyers
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

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.

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