Isolation of genes encoding NF-kB activator in adult T-cell leukemia

人类T细胞白血病病毒1型(HTLV-1)与成人T细胞白血病(ATL)的发生有关。HTLV-1编码的Taxi癌蛋白通过核因子-kB途径激活细胞生长和抗凋亡相关基因的转录，被认为在ATL的发病机制中起关键作用。虽然ATL细胞中Tax1的表达通常缺失或很少，但这些细胞仍然显示出高的组成性核因子-kB活性，这表明ATL细胞的遗传或表观遗传变化诱导了独立于Tax1的激活。这项研究的目的是利用逆转录病毒功能克隆策略确定在ATL细胞中负责核因子-kB结构性激活的分子。以增强型绿色荧光蛋白(EGFP)表达和杀菌素抗性为选择标记，从ATL细胞系中获得了包括全长CD30在内的多个在大鼠1细胞中具有组成性核因子-kB活性的逆转录病毒克隆。外源性稳定表达CD30的大鼠-1细胞可结构性激活核因子-kB。CD30在所有转化的ATL和HTLV-1转化的T细胞系以及来自少数患者的原代ATL细胞中均有高表达。CD30的高表达被认为是ATL细胞结构性核因子-kB活化的原因之一，并可能参与ATL的发生发展。

Human T-cell leukemia virus type 1(HTLV-1) is associated with the development of adult T-cell leukemia(ATL). HTLV-1 encoded Taxi oncoprotein activates the transcription of genes involved in cell growth and anti-apoptosis through the NF-kB pathway, and is thought to play a critical role in the pathogenesis of ATL. While Tax1 expression is usually lost or minimal in ATL cells, these cells still show high constitutive NF-kB activity, indicating that genetic or epigenetic changes in ATL cells induce activation independent of Tax1. The aim of this study was to identify the molecules responsible for the constitutive activation of NF-kB in ATL cells using a retroviral functional cloning strategy. Using enhanced green fluorescent protein(EGFP) expression and blasticidin-resistance as selection markers, several retroviral cDNA clones exhibiting constitutive NF-kB activity in Rat-1 cells, including full-length CD30, were obtained from an ATL cell line. Exogenous stable expression of CD30 in Rat-1 cells constitutively activated NF-kB. Elevated expression of CD30 was identified in all ATL and HTLV-1 transformed T-cell lines examined, and primary ATL cells from a small number of patients. Elevated CD30 expression is considered one of the causes of constitutive NF-kB activation in ATL cells, and may be involved in ATL development.