Evidence for distinct pathomechanisms in genetic subgroups of chronic lymphocytic leukemia revealed by quantitative expression analysis of cell cycle, activation, and apoptosis-associated genes
Evidence for distinct pathomechanisms in genetic subgroups of chronic lymphocytic leukemia revealed by quantitative expression analysis of cell cycle, activation, and apoptosis-associated genes
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DOI：
10.1200/jco.2005.02.568
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发表时间：
2005-06-01
影响因子：
45.3
通讯作者：
Stilgenbauer, S
中科院分区：
文献类型：
--
作者：
Kienle, DL;Korz, C;Stilgenbauer, S
目的在慢性淋巴细胞白血病(CLL)患者中，VH基因突变状态和基因组突变(13q-、+12c、11q-、17p-)可识别不同的预后亚群。方法采用实时定量逆转录聚合酶链式反应(RQ-PCR)技术，对82例慢性淋巴细胞性白血病(CLL)中与细胞凋亡、细胞周期、B细胞活化和B细胞受体(BCR)信号转导相关的24个基因进行了分析，根据VH基因突变状态和基因组13q-、+12、11q-、17p-的突变情况，确定了典型的遗传性CLL亚群。在由基因组异常定义的亚群中，受影响的关键基因组区域的候选基因如CDK4(向上)、ATM(向下)和TP53(向下)分别在+12、11q-和17p-组中被解除调控。此外，基因组亚群的特征是13q的AKT(上调)，+12的E2F1(上调)，17p-的MYC(上调)和bcl2(下调)，11q-的CCND3(下调)以及17p-的CCND3(下调)。17p亚组中SYK和PI3K等bcr相关基因的表达水平进一步下调。结论所观察到的特征性基因表达模式提示在不同的基因亚组中对细胞周期、细胞凋亡和bcr信号的调控存在差异，说明CLL具有不同的发病机制，并为基因剂量效应在CLL中发挥作用提供了证据。这些发现将CLL的生物学多样性和临床异质性联系在一起。
Purpose In patients with chronic lymphocytic leukemia (CLL), the VH mutation status and genomic aberrations (13q-, +12c, 11q-, 17p-) identify distinct prognostic subgroups. The aim was to elucidate biologic mechanisms through which these genetic markers may exert their pathogenic influence.Patients and Methods Twenty-four genes involved in apoptosis, cell cycle, B-cell activation, and B-cell receptor (BCR) signaling were analyzed by real-time quantitative reverse transcription polymerase chain reaction.(RQ-PCR) in 82 CLL cases constituting prototypic genetic CLL subgroups as defined by the VH mutation status and the genomic aberrations 13q-, +12, 11q-, and 17p-.Results The VH mutation subgroups were characterized by a differential expression of the BCR associated genes ZAP70 and PI3K. Among the subgroups defined by genomic aberrations, there was a deregulation of candidate genes from the affected critical genomic regions such as CDK4 (up), ATM (down), and TP53 (down) in the groups +12, 11q-, and 17p-, respectively. Additionally, the genomic subgroups were characterized by a significant deregulation of cell cycle and apoptosis regulators AKT(up) in 13q, E2F1 (up) in + 12, MYC (up) and BCL-2 (down) in 17p-, and CCND3 (down) in 11q- as well as 17p-. The 17p- subgroup showed an additional down-regulation of BCR-associated genes such as SYK and PI3KConclusion The characteristic gene expression patterns observed implicate a differential regulation of cell cycle, apoptosis, and BCR signaling in the genetic subgroups illustrating distinct pathomechanisms and are evidence for a gene dosage effect being operative in CLL. These findings link the biologic diversity and clinical heterogeneity of CLL.