Mittal Amit K, Hegde Ganapati V, Aoun Patricia, Bociek Robert G, Dave Bhavana J, Joshi Avadhut D, Sanger Warren G, Weisenburger Dennis D, Joshi Shantaram S
Department of Genetics, University of Nebraska Medical Center, Omaha, NE 68198-6395, USA.
Int J Mol Med. 2007 Oct;20(4):461-9.
In B-cell chronic lymphocytic leukemia (CLL), Rai stage, immunoglobulin gene mutational status, chromosomal abnormalities, CD38 and ZAP-70 expression were used as prognostic markers. In this study, to understand the molecular basis of chromosomal abnormalities leading to tumor progression, 90 CLL patients were grouped into poor prognosis (with 11q deletion and trisomy 12) and good prognosis (with normal karyotype and 13q deletion) and their clinical outcome was assessed. Gene expression profiles of 35 CLL samples with poor outcome (11q deletion, n=9; trisomy 12, n=5) and good outcome (13q deletion, n=13; normal karyotype, n=8) were analyzed using oligonucleotide microarray. Significance analysis of microarray (SAM) identified 27 differentially expressed genes between these two subgroups with significant overexpression of ATF5 and underexpression of CDC16, PCDH8, SLAM, MNDA and ATF2 in CLL patients with poor outcome. ATF5 gene expression in CLL was further studied because of its role in the regulation of cell cycle progression/differentiation and apoptosis. The overexpression of ATF5 was confirmed by real-time PCR using 39 CLL samples from the poor and good outcome groups. ATF5 was significantly (p<0.001) overexpressed in the poor outcome group. Furthermore, ATF5 expression was significantly higher in the 11q deletion as well as trisomy 12 group alone compared to the 13q deletion and normal karyotype groups. ATF5 overexpression was also associated with significantly (p=0.04) shorter time to treatment. Similarly, expression of five underexpressed genes also correlated with longer time to treatment. Thus, this report demonstrates that ATF5 may be one of the key genes involved in increased proliferation and survival in 11q deletion or trisomy 12, whereas CD16, CD86, SLAM, MNDA and ATF2 may be involved in the decreased proliferation of CLL cells with 13q deletion or normal karyotype.
在B细胞慢性淋巴细胞白血病（CLL）中，Rai分期、免疫球蛋白基因突变状态、染色体异常、CD38和ZAP - 70表达被用作预后标志物。在本研究中，为了解导致肿瘤进展的染色体异常的分子基础，将90例CLL患者分为预后不良组（有11q缺失和12号染色体三体）和预后良好组（核型正常和13q缺失），并评估其临床结局。使用寡核苷酸微阵列分析了35例预后不良（11q缺失，n = 9；12号染色体三体，n = 5）和预后良好（13q缺失，n = 13；核型正常，n = 8）的CLL样本的基因表达谱。微阵列显著性分析（SAM）确定了这两个亚组之间27个差异表达基因，在预后不良的CLL患者中，ATF5显著过表达，而CDC16、PCDH8、SLAM、MNDA和ATF2表达不足。由于ATF5在细胞周期进程/分化和凋亡调节中的作用，对其在CLL中的基因表达进行了进一步研究。使用来自预后不良和良好组的39例CLL样本通过实时PCR证实了ATF5的过表达。ATF5在预后不良组中显著（p < 0.001）过表达。此外，与13q缺失和核型正常组相比，单独的11q缺失以及12号染色体三体组中ATF5表达显著更高。ATF5过表达还与显著（p = 0.04）更短的治疗时间相关。同样，五个表达不足基因的表达也与更长的治疗时间相关。因此，本报告表明，ATF5可能是参与11q缺失或12号染色体三体中增殖增加和存活的关键基因之一，而CD16、CD86、SLAM、MNDA和ATF2可能参与13q缺失或核型正常的CLL细胞增殖减少。
