Kalla Claudia, Scheuermann Markus O, Kube Ina, Schlotter Magdalena, Mertens Daniel, Döhner Hartmut, Stilgenbauer Stephan, Lichter Peter
Division of Molecular Genetics, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Eur J Cancer. 2007 May;43(8):1328-35. doi: 10.1016/j.ejca.2007.02.005. Epub 2007 Apr 20.
Deletion of 11q22-q23 is associated with an aggressive course of B-cell chronic lymphocytic leukaemia (B-CLL). Since only in a subset of these cases biallelic inactivation of ATM was observed, we sought to identify other disease-associated genes within 11q22-q23 by analysing NPAT (cell-cycle regulation), CUL5 (ubiquitin-dependent apoptosis regulation) and PPP2R1B (component of the cell-cycle and apoptosis regulating PP2A) for point mutations and their expression in B-CLL by single-strand conformation polymorphism/sequence analysis of the transcripts and real-time polymerase chain reaction. Though none of the genes were affected by deleterious mutations, we observed a significant down-regulation of NPAT in B-CLL versus CD19+ B cells and of CUL5 in 11q deletion versus non-deletion B-CLL samples and measured reduced PPP2R1B transcript levels in a subset of B-CLL cases. Alternative splicing of PPP2R1B transcripts (skipping of exons 2/3, 3, 9) was associated with a reduced activity of protein phosphatase 2A. Together, these results implicate deregulation of the cell-cycle and apoptosis regulators NPAT, CUL5 and PPP2R1B and a role for these genes in the pathogenesis of B-CLL.
11q22 - q23缺失与B细胞慢性淋巴细胞白血病（B - CLL）的侵袭性病程相关。由于仅在这些病例的一个子集中观察到ATM的双等位基因失活，我们试图通过分析NPAT（细胞周期调控）、CUL5（泛素依赖性凋亡调控）和PPP2R1B（细胞周期和凋亡调控的PP2A的组成部分）的点突变及其在B - CLL中的表达，来鉴定11q22 - q23内的其他疾病相关基因，方法是通过转录本的单链构象多态性/序列分析和实时聚合酶链反应。尽管这些基因均未受到有害突变的影响，但我们观察到与CD19 + B细胞相比，B - CLL中NPAT显著下调，与非11q缺失的B - CLL样本相比，11q缺失的B - CLL样本中CUL5下调，并且在一部分B - CLL病例中检测到PPP2R1B转录水平降低。PPP2R1B转录本的可变剪接（外显子2/3、3、9的跳过）与蛋白磷酸酶2A的活性降低有关。总之，这些结果表明细胞周期和凋亡调节因子NPAT、CUL5和PPP2R1B失调，并且这些基因在B - CLL的发病机制中起作用。
