Hiebert S W, Sun W, Davis J N, Golub T, Shurtleff S, Buijs A, Downing J R, Grosveld G, Roussell M F, Gilliland D G, Lenny N, Meyers S
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Mol Cell Biol. 1996 Apr;16(4):1349-55. doi: 10.1128/MCB.16.4.1349.
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.
在高达30%的儿童B细胞急性淋巴细胞白血病中存在t(12;21)易位，它将ets相关因子TEL的一个潜在二聚化基序与AML1的N端融合。t(12;21)易位编码一种93 kDa的融合蛋白，该蛋白定位于耐高盐和去污剂的核区室。这种蛋白结合增强子核心基序TGTGGT，并与AML-1结合蛋白核心结合因子β相互作用。虽然TEL/AML-1B保留了T细胞受体β增强子反式激活所需的AML-1B的C端结构域，但它不能激活转录，反而抑制该增强子的基础活性。TEL/AML-1B有效干扰AML-1B依赖的T细胞受体β增强子的反式激活，野生型TEL的共表达不能逆转这种抑制作用。N端TEL螺旋-环-螺旋结构域对于TEL/AML-1B介导的抑制至关重要。因此，t(12;21)融合蛋白主要干扰AML-1B依赖的转录，提示AML-1基因表达的抑制对于B细胞白血病发生至关重要。
