THE T(12-21) TRANSLOCATION CONVERTS AML-1B FROM AN ACTIVATOR TO A REPRESSOR OF TRANSCRIPTION

The t(12;21) translocation is present in up to 30% of childhood B-cell acute lymphoblastic leukemias and fuses a potential dimerization moti f 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 b inds the enhancer core motif, TGTGGT, and interacts with the AML-l-bin ding protein, core-binding factor beta. Although TEL/AML-1B retains th e 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 ef ficiently interferes with AML-1B-dependent transactivation of the T-ce ll 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) fusi on protein dominantly interferes with AML-1B-dependent transcription, suggesting that the inhibition of expression of AML-1 target genes is critical for B-cell leukemogenesis.