Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin
Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin
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DOI：
10.1182/blood-2002-01-0189
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发表时间：
2003-01-01
期刊：
影响因子：
20.3
通讯作者：
Peschel, C
中科院分区：
文献类型：
--
作者：
Decker, T;Hipp, S;Peschel, C
在B细胞慢性淋巴细胞白血病（B-CLL）中，恶性细胞似乎被阻滞在细胞周期的G（0）/早期G（1）期，并且缺陷性凋亡可能参与疾病进展。然而，越来越多的证据表明，B-CLL不仅仅是一种由缓慢积累的静息B细胞组成的疾病：淋巴结和骨髓中的细胞增殖池已被描述，并可能为血液中的积累池提供营养。据报道，雷帕霉素可抑制多种细胞类型（包括人B细胞）的细胞周期进程，并显示出对广泛的人肿瘤细胞系的活性。因此，我们研究了雷帕霉素在增殖的B-CLL细胞中阻断细胞周期进程的能力。我们最近已经证明，刺激与CpG-寡核苷酸和白细胞介素-2提供了一个有价值的模型，研究恶性B细胞的细胞周期调控。在我们目前的研究中，我们证明了雷帕霉素诱导增殖的B-CLL细胞的细胞周期阻滞，并抑制p70 s6激酶（P70（s6 k））磷酸化。与以前报道的非恶性B细胞相反，雷帕霉素处理的白血病细胞中细胞周期抑制剂p27的表达没有改变。用雷帕霉素处理阻止了B-CLL细胞中视网膜母细胞瘤蛋白（RB）的磷酸化，而不影响细胞周期蛋白D2的表达，但在雷帕霉素处理的B-CLL细胞中不再检测到细胞周期蛋白D3。此外，雷帕霉素处理通过阻止细胞周期蛋白E和细胞周期蛋白A的上调来抑制细胞周期蛋白依赖性激酶2的活性。有趣的是，生存素，这是在体内的B-CLL患者的增殖中心表达，在雷帕霉素处理的细胞中没有上调。因此，雷帕霉素干扰了许多关键分子的表达，用于周期性B-CLL细胞中的细胞周期调控。我们的结论是，雷帕霉素可能是一种有吸引力的物质，用于治疗B-CLL患者，诱导增殖肿瘤细胞的G1阻滞。(C)2003年，美国血液学会。
In B-cell chronic lymphocytic leukemia (B-CLL), malignant cells seem to be arrested in the G(0)/early G(1) phase of the cell cycle, and defective apoptosis might be involved in disease progression. However, increasing evidence exists that B-CLL is more than a disease consisting of slowly accumulating resting B cells: a proliferating pool of cells has been described in lymph nodes and bone marrow and might feed the accumulating pool in the blood. Rapamycin has been reported to inhibit cell cycle progression in a variety of cell types, including human B cells, and has shown activity against a broad range of human tumor cell lines. Therefore, we investigated the ability of rapamycin to block cell cycle progression in proliferating B-CLL cells. We have recently demonstrated that stimulation with CpG-oligonucleotides and interleukin-2 provides a valuable model for studying cell cycle regulation in malignant B cells. In our present study, we demonstrated that rapamycin induced cell cycle arrest in proliferating B-CLL cells and inhibited phosphorylation of p70s6 kinase (P70(s6k)). In contrast to previous reports on nonmalignant B cells, the expression of the cell cycle inhibitor p27 was not changed in rapamycin-treated leukemic cells. Treatment with rapamycin prevented retinoblastoma protein (RB) phosphorylation in B-CLL cells without affecting the expression of cyclin D2, but cyclin D3 was no longer detectable in rapamycin-treated B-CLL cells. In addition, rapamycin treatment inhibited cyclin-dependent kinase 2 activity by preventing up-regulation of cyclin E and cyclin A. Interestingly, survivin, which is expressed in the proliferation centers of B-CLL patients in vivo, is not up-regulated in rapamycin-treated cells. Therefore, rapamycin interferes with the expression of many critical molecules for cell cycle regulation in cycling B-CLL cells. We conclude from our study that rapamycin might be an attractive substance for therapy for B-CLL patients by inducing a G, arrest in proliferating tumor cells. (C) 2003 by The American Society of Hematology.