Mantle cell lymphomas lack expression of p27kip1, a cyclin-dependent kinase inhibitor
Mantle cell lymphomas lack expression of p27kip1, a cyclin-dependent kinase inhibitor
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DOI：
10.1016/s0002-9440(10)65558-7
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发表时间：
1998-07-01
影响因子：
6
通讯作者：
Raffeld, M
中科院分区：
文献类型：
--
作者：
Quintanilla-Martinez, L;Thieblemont, C;Raffeld, M
p27（Kip1）是一种周期蛋白依赖性激酶抑制剂，调节细胞进入S期或退出细胞周期的决定。在静息细胞中，p27（Kip1）水平提供了一个抑制阈值，高于该阈值，G1周期蛋白D/E/周期蛋白依赖性激酶在激活前积累；然而，在循环细胞中，p27（Kip1）蛋白被高水平的活性周期蛋白D/周期蛋白依赖性激酶4复合物隔离。作为一个群体，周期蛋白依赖性激酶抑制剂已被提出作为肿瘤抑制基因，并且一些成员已涉及多种人类癌症的发病机制。我们检测了p27（Kip1）在116例非霍奇金淋巴瘤中的表达，包括50例MCL（40例典型和10例胚性变异）、21例滤泡性淋巴瘤、20例弥漫性大b细胞淋巴瘤、16例慢性淋巴细胞白血病、8例边缘区b细胞淋巴瘤和1例脾边缘区淋巴瘤，并将其表达与增殖标志物Ki67 （MiB1）和p53的表达进行了相关性分析。在除MCL外的所有非霍奇金淋巴瘤病例中，p27（Kip1）的表达与Ki67测量的增殖指数呈负相关。相反，在典型的MCL中，40例中有35例（88%）的p27（Kip1）表达为阴性，与增殖率无关（中位数15%；范围2 - 90%）。矛盾的是，在MCL的母细胞变体中，10例中有8例（80%）显示p27（Kip1）的表达，尽管增殖率很高（中位数为60%；范围为52%至100%）。然而，大多数病例的染色强度低于反应性T淋巴细胞，25例病例中均未发现p27（Kip1）基因缺失。50例MCL中有15例p53表达，10例中有7例（70%）在母细胞型MCL中表达，40例中有8例（20%）在典型MCL中表达（70% vs. 20%, P < 0.0045）。这些结果表明，与其他非霍奇金淋巴瘤和正常淋巴组织相比，MCL中p27（Kip1）的表达与增殖率没有相关性。这种p27（Kip1）蛋白表达与增殖速率的特殊解耦可能与MCL中cyclin D1的高水平表达有关，并可能对细胞周期调节产生深远影响，并参与MCL的发病机制。
p27(Kip1) is a cyclin-dependent kinase inhibitor that regulates the decision to enter S phase or withdraw from the cell cycle. In resting cells, the level of p27(Kip1) provides an inhibitory threshold above which G1 cyclin D/E/cyclin-dependent kinases accumulate before activation; however, in cycling cells, p27(Kip1) protein is sequestered by high levels of active cyclin D/cyclin-dependent kinase 4 complexes. As a group, the cyclin-dependent kinase inhibitors have been proposed to act as tumor suppressor genes, and several members have been implicated in the pathogenesis of a variety of human cancers. We examined p27(Kip1) expression in 116 non-Hodgkin's lymphomas including 50 cases of MCL (40 typical and 10 blastic variants), 21 follicular lymphomas, 20 diffuse large B-cell lymphomas, 16 chronic lymphocytic leukemias, 8 marginal zone B-cell lymphomas, and 1 splenic marginal zone lymphoma, and correlated its expression with that of the proliferation marker Ki67 (MiB1) and with p53. p27(Kip1) gene structure was analyzed by Southern blot in the group of MCLs, In all cases of non-Hodgkin's lymphoma other than MCL, p27(Kip1) expression was inversely related to the proliferation index as measured by Ki67, In contrast, in typical MCL, p27(Kip1) expression was negative in 35 of 40 (88%) cases, irrespective of the proliferative rate (median 15%; range 2 to 90%). Paradoxically, in the blastic variant of MCL, 8 of 10 (80%) cases showed expression of p27(Kip1), despite a high proliferation rate (median 60%; range 52 to 100%). However, the staining in most of the cases was less intense than in the reactive T lymphocytes, Deletions of p27(Kip1) gene were not found in any of the 25 cases examined. p53 expression was found in 15 of 50 cases of MCL: 7 of 10 (70%) in the blastic variant and 8 of 40 (20%) in the typical MCL (70% vs. 20%, P < 0.0045), These results demonstrate that MCLs, in contrast to other non-Hodgkin's lymphomas and normal lymphoid tissue, fail to correlate p27(Kip1) expression with the proliferation rate. This peculiar uncoupling of p27(Kip1) protein expression from the proliferation rate may be related to the high levels of cyclin D1 expressed in MCL and is likely to have profound effects on cell cycle regulation and contribute to the pathogenesis of MCL.