Cancer Biology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
Leukemia. 2011 Oct;25(10):1578-86. doi: 10.1038/leu.2011.140. Epub 2011 Jun 7.
The transcription factor T-cell acute lymphocytic leukemia (TAL)-1 is a major T-cell oncogene associated with poor prognosis in T-cell acute lymphoblastic leukemia (T-ALL). TAL1 binds histone deacetylase 1 and incubation with histone deacetylase inhibitors (HDACis) promotes apoptosis of leukemia cells obtained from TAL1 transgenic mice. Here, we show for the first time that TAL1 protein expression is strikingly downregulated upon histone deacetylase inhibition in T-ALL cells. This is due to decreased TAL1 gene transcription in cells with native TAL1 promoter, and due to impaired TAL1 mRNA translation in cells that harbor the TAL1(d) microdeletion and consequently express TAL1 under the control of the SCL/TAL1 interrupting locus (SIL) promoter. Notably, HDACi-triggered apoptosis of T-ALL cells is significantly reversed by TAL1 forced overexpression. Our results indicate that the HDACi-mediated apoptotic program in T-ALL cells is partially dependent on their capacity to downregulate TAL1 and provide support for the therapeutic use of HDACi in T-ALL.
转录因子 T 细胞急性淋巴细胞白血病（TAL）-1 是与 T 细胞急性淋巴细胞白血病（T-ALL）预后不良相关的主要 T 细胞癌基因。TAL1 与组蛋白去乙酰化酶 1 结合，与组蛋白去乙酰化酶抑制剂（HDACi）孵育可促进 TAL1 转基因小鼠白血病细胞的凋亡。在这里，我们首次表明，在 T-ALL 细胞中抑制组蛋白去乙酰化酶可显著下调 TAL1 蛋白表达。这是由于天然 TAL1 启动子细胞中的 TAL1 基因转录减少，以及携带 TAL1(d)微缺失的细胞中 TAL1 mRNA 翻译受损，从而在 SCL/TAL1 中断基因座（SIL）启动子的控制下表达 TAL1。值得注意的是，TAL1 强制过表达可显著逆转 HDACi 触发的 T-ALL 细胞凋亡。我们的结果表明，HDACi 在 T-ALL 细胞中的凋亡程序部分依赖于其下调 TAL1 的能力，并为 HDACi 在 T-ALL 中的治疗用途提供支持。
