Chromosomal instability in the multi-step carcinogenesis of adult T-cell leukemia/lymphoma

成人T细胞白血病/淋巴瘤(ATL)与人类T淋巴细胞白血病病毒1型(HTLV-1)相关。为了解ATL慢性期到急性期进展过程中基因表达的变化，采用高密度寡核苷酸芯片比较了4对新鲜ATL细胞的基因表达谱。我们鉴定了203个在急性期和慢性期样本中普遍上调的基因，包括核糖体蛋白、蛋白体亚单位、真核翻译因子、免疫亲和素、热休克蛋白和对DNA复制重要的基因。此外，我们确定了91个普遍下调的基因，包括与MHC和一种磷酸酶相关的免疫分子。此前已确定其中几个基因与HTLV-1的Tax蛋白有关。在相应的慢性/急性ATL样本中，一些上调的基因位于比较基因组杂交所确定的扩增区域。利用实时荧光定量聚合酶链式反应，对芯片分析结果进行了验证。这些结果表明，在ATL向急性期的转变过程中，已知在细胞转化和/或激活以及染色体不稳定中起关键作用的不同的基因集被上调或下调。

Adult T-cell leukemia/lymphoma(ATL) is associated with human T-lymphotropic virus type-1(HTLV-1). To understand the changes in expression that occur in the progression of chronic phase of ATL to acute crisis, the gene expression profiles of fresh ATL cells were compared in 4 pairs of samples (progression of chronic to acute phase in 3 patients, as well as one typical chronic phase sample versus one typical acute phase sample) using high density oligonucleotide DNA arrays. We identified 203 genes that were commonly up-regulated in acute versus chronic phase samples including ribosomal proteins, proteosome subunits, eukaryotic translation factors, immunophilins, heat shock proteins and genes important for DNA replication. Additionally, we identified 91 commonly down-regulated genes including immune molecules related to MHC and a phosphatase. Several of the genes were previously identified to be associated with the Tax protein of HTLV-1. Some of the up-regulated genes were located in amplified regions identified by comparative genomic hybridization in the corresponding chronic/acute ATL sample. Using real-time quantitative PCR, we confirmed the array-results in those specimens analyzed by microarray. These results demonstrated that distinct sets of genes that are known to be critical in cellular transformation and/or activation as well as chromosomal instability are up- or down-regulated during the transition to the acute phase of ATL.