Anderegg B, Horstmann M, Kabisch H
Department of Hematology/Oncology, Children's Hospital, Clinical Center for the University of Hamburg, Germany.
Cancer Gene Ther. 1997 Mar-Apr;4(2):84-90.
Rearrangement of the gene tal-1 leads to transcriptional dysregulation and contributes to the formation of childhood T-cell acute lymphoblastic leukemia. Therefore, we tried to interfere with the transcription of the SIL/tal-1 fusion gene, the most common form of aberrant tal-1, by treatment with antisense oligodeoxynucleotides (ODNs). The potential of two different strategies was investigated, one targeting the cell line specific SIL/tal-1 fusion region, the other using an ODN complementary to tal-1 sequence downstream of the region not affected by any of the known types of tal-1 rearrangement. With both approaches a single-dose application of 3 mumol of ODN led to a significant antiproliferative effect of a about 25-60% in two T-ALL cell lines characterized by the SIL/tal-1 fusion gene. Investigation of the tal-1 mRNA level by reverse transcription-polymerase chain reaction was in concordance with these results: In both cell lines clearly less of the tal-1-specific fragment was generated after incubation with the antisense ODN tal-1 common than in the control experiments with a mismatched ODN or no ODN at all. Neither the antiproliferation antisense effect nor the downregulation of the steady state tal-1 mRNA level was observed in control cell lines bearing wildtype tal-1.
基因tal-1的重排导致转录失调，并促使儿童T细胞急性淋巴细胞白血病的形成。因此，我们尝试通过用反义寡脱氧核苷酸（ODN）处理来干扰SIL/tal-1融合基因（tal-1异常的最常见形式）的转录。研究了两种不同策略的潜力，一种靶向细胞系特异性SIL/tal-1融合区域，另一种使用与不受任何已知类型tal-1重排影响的区域下游的tal-1序列互补的ODN。两种方法中，单剂量应用3 μmol的ODN在两个以SIL/tal-1融合基因为特征的T-ALL细胞系中均产生了约25% - 60%的显著抗增殖作用。通过逆转录 - 聚合酶链反应对tal-1 mRNA水平的研究与这些结果一致：在两个细胞系中，与反义ODN tal-1 common孵育后产生的tal-1特异性片段明显少于与错配ODN或根本不使用ODN的对照实验。在携带野生型tal-1的对照细胞系中未观察到抗增殖反义效应或稳态tal-1 mRNA水平的下调。
