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）的发展有关。HTLV-1编码的Taxi癌蛋白通过NF-kB通路激活参与细胞生长和抗凋亡的基因转录，被认为在ATL的发病机制中起关键作用。虽然在ATL细胞中，Tax1的表达通常缺失或极少，但这些细胞仍然显示出高组成NF-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。本研究的目的是利用逆转录病毒功能克隆策略确定负责ATL细胞中NF-kB组成性激活的分子。利用增强的绿色荧光蛋白（EGFP）表达和抗囊胚素作为选择标记，从ATL细胞系中获得了几个在大鼠-1细胞中具有组成性NF-kB活性的逆转录病毒cDNA克隆，包括全长CD30。外源性CD30在大鼠-1细胞中的稳定表达构成性激活NF-kB。CD30在所有ATL和HTLV-1转化的t细胞系以及少数患者的原代ATL细胞中表达升高。CD30表达升高被认为是ATL细胞组成性NF-kB激活的原因之一，并可能参与ATL的发展。

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.