Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12461-6. doi: 10.1073/pnas.1018941108. Epub 2011 Jul 11.
The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G(1)-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors.
导致 cyclin-D1 过表达的染色体易位 t(11;14)(q13;q32) 在套细胞淋巴瘤 (MCL) 的发展中起着至关重要的作用，这是一种侵袭性肿瘤，目前的治疗策略仍然无法治愈。Cyclin-D1 已被推测为一种有效的治疗靶点，但由于我们对其致癌功能的理解不完整，以及缺乏有效的 MCL 小鼠模型，该靶点的评估受到了阻碍。为了解决这些问题，我们生成了一个 cyclin-D1 驱动的小鼠模型，其中 cyclin-D1 的表达可以外部调控。这些小鼠发展出表达 cyclin-D1 的淋巴瘤，能够重现人类 MCL 的特征。我们发现 cyclin-D1 的失活不足以在体内诱导淋巴瘤消退；然而，通过体外和体内实验的组合，我们在 MCL 细胞中发现了 cyclin-D1 的一种新的促生存功能。具体来说，我们发现 cyclin-D1 除了通过在 G1-S 转换时对细胞周期的失调来增加细胞增殖外，还将促凋亡蛋白 BAX 隔离在细胞质中，从而有利于 BCL2 的抗凋亡功能。因此，cyclin-D1 抑制通过 BAX 的释放使淋巴瘤细胞对凋亡敏感。因此，cyclin-D1 的遗传或药理学靶向与促凋亡 BH3 模拟物联合协同杀死表达 cyclin-D1 的小鼠淋巴瘤、人类 MCL 细胞系和原发性淋巴瘤细胞。我们的研究确定了 cyclin-D1 在调节 MCL 细胞凋亡中的作用，并强调了同时针对 cyclin-D1 和生存途径在 MCL 患者中的潜在益处。这种有效的联合治疗策略也可能在其他表达 cyclin-D1 的肿瘤中得到利用。
