Kienle Dirk L, Korz Christian, Hosch Beate, Benner Axel, Mertens Daniel, Habermann Annett, Kröber Alexander, Jäger Ulrich, Lichter Peter, Döhner Hartmut, Stilgenbauer Stephan
Department of Internal Medicine III, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany.
J Clin Oncol. 2005 Jun 1;23(16):3780-92. doi: 10.1200/JCO.2005.02.568. Epub 2005 May 2.
In patients with chronic lymphocytic leukemia (CLL), the VH mutation status and genomic aberrations (13q-, +12q, 11q-, 17p-) identify distinct prognostic subgroups. The aim was to elucidate biologic mechanisms through which these genetic markers may exert their pathogenic influence.
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-.
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 PI3K.
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.
在慢性淋巴细胞白血病（CLL）患者中，VH突变状态和基因组畸变（13q-、+12q、11q-、17p-）可识别不同的预后亚组。本研究旨在阐明这些遗传标志物可能发挥致病影响的生物学机制。
通过实时定量逆转录聚合酶链反应（RQ-PCR）分析了82例CLL患者中涉及凋亡、细胞周期、B细胞活化和B细胞受体（BCR）信号传导的24个基因，这些患者构成了由VH突变状态和基因组畸变13q-、+12、11q-和17p-定义的典型遗传性CLL亚组。
VH突变亚组的特征是BCR相关基因ZAP70和PI3K的表达存在差异。在由基因组畸变定义的亚组中，+12、11q-和17p-组中分别存在来自受影响关键基因组区域的候选基因失调，如CDK4（上调）、ATM（下调）和TP53（下调）。此外，基因组亚组的特征是细胞周期和凋亡调节因子的显著失调：13q组中的AKT（上调）、+12组中的E2F1（上调）、17p-组中的MYC（上调）和BCL-2（下调），以及11q-和17p-组中的CCND3（下调）。17p-亚组还显示出BCR相关基因如SYK和PI3K的额外下调。
观察到的特征性基因表达模式表明，遗传亚组中细胞周期、凋亡和BCR信号传导存在差异调节，说明了不同的发病机制，并且是CLL中存在基因剂量效应的证据。这些发现将CLL的生物学多样性与临床异质性联系起来。
