Cell cycle progression of chronic lymphocytic leukemia cells is controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and the cdk inhibitor p27
Cell cycle progression of chronic lymphocytic leukemia cells is controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and the cdk inhibitor p27
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DOI：
10.1038/sj.leu.2402389
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发表时间：
2002-03-01
期刊：
影响因子：
11.4
通讯作者：
Peschel, C
中科院分区：
文献类型：
--
作者：
Decker, T;Schneller, F;Peschel, C
B-CLL细胞被阻滞在细胞周期的G 0/早期G1期，其特征在于对多种多克隆B细胞活化剂具有显著的低反应性。我们以前已经证明，用CpG-ODN和IL-2共刺激可以克服这种增殖缺陷。细胞周期蛋白D3是介导正常B细胞中G1期进展的主要D型细胞周期蛋白，但在B-CLL细胞中，细胞周期蛋白D2和细胞周期蛋白D3在刺激后均强烈上调。两种细胞周期蛋白均与cdk 4相关，但与cdk 6无关，后者是正常B细胞中D型细胞周期蛋白的催化伴侣。此外，由细胞周期蛋白D2和cdk 4或细胞周期蛋白D3和cdk 4组成的免疫复合物在体外都是功能性的并且磷酸化RB蛋白。细胞周期抑制剂p27在B淋巴细胞的细胞周期进展中起关键作用，并且已显示在B-CLL细胞中过表达。P27在B-CLL细胞中迅速下调，即使用单独的非CpG-ODN或IL-2刺激，而在正常B细胞中仅可观察到中度调节。综上所述，我们的研究结果表明，早期细胞周期进程的调节B-CLL细胞和正常B细胞之间的不同。这些发现不仅有助于理解B-CLL的病理生理学，而且可能最终导致新的治疗靶点的确定。
B-CLL cells are arrested in G0/early G1 phase of the cell cycle and are characterized by a marked hyporesponsiveness towards a variety of polyclonal B cell activators. We have previously demonstrated that costimulation with CpG-ODN and IL-2 can overcome this proliferative defect. Cyclin D3 is the principal D-type cyclin which mediates G1 progression in normal B cells, but in B-CLL cells both cyclin D2 and cyclin D3, were strongly upregulated upon stimulation. Both cyclins were associated with cdk4 but not with cdk6, which is the catalytic partner of D-type cyclins in normal B cells. Moreover, immune complexes consisting of cyclin D2 and cdk4 or cyclin D3 and cdk4 were both functional and phosphorylated the RB protein in vitro. The cell cycle inhibitor p27 plays a pivotal role in cell cycle progression of B lymphocytes and has been shown to be overexpressed in B-CLL cells. P27 was rapidly downregulated in B-CLL cells even when stimulated with a non-CpG-ODN or IL-2 alone, while only moderate regulation could be observed in normal B cells. Taken together, our findings demonstrate that regulation of early cell cycle progression differs between B-CLL cells and normal B cells. These findings do not only contribute to the understanding of B-CLL pathophysiology, but might ultimately lead to the identification of new therapeutic targets.