Krajewski S, Bodrug S, Gascoyne R, Berean K, Krajewska M, Reed J C
La Jolla Cancer Research Foundation, California.
Am J Pathol. 1994 Sep;145(3):515-25.
The Bcl-2 protein blocks programmed cell death and becomes overproduced in many follicular non-Hodgkin's lymphomas as the result of t(14; 18) translocations involving the Bcl-2 gene. Mcl-1 is a recently discovered gene whose encoded protein has significant homology with Bcl-2 but whose function remains unknown. In this study, we compared the in vivo patterns of Bcl-2 and Mcl-1 protein production in normal and neoplastic lymph node biopsies by immunohistochemical means using specific polyclonal antisera. Intracellular Mcl-1 immunoreactivity was located primarily in the cytosol in a punctate pattern and was also seen in association with the nuclear envelope in many cases, similar to the results obtained for Bcl-2, which resides in the outer mitochondrial membrane, nuclear envelope, and endoplasmic reticulum. In 4 of 4 reactive tonsils and 28 of 28 nodes with reactive follicular hyperplasia, reciprocal patterns of Bcl-2 and Mcl-1 protein expression were observed. Bcl-2 immunostaining was highest in mantle zone lymphocytes and absent from most germinal center cells, whereas Mcl-1 immunoreactivity was highest in germinal center lymphocytes and absent from mantle zone lymphocytes. Mcl-1 was also expressed in some interfollicular lymphocytes, particularly those that had the appearance of activated lymphocytes. Similar to the patterns of Bcl-2 and mcl-1 expression seen in reactive nodes, Mcl-1 protein was largely absent from the malignant cells in 2 of 2 mantle cell lymphomas, whereas strong Bcl-2 immunostaining was found in these cells. In contrast to normal nodes, however, the neoplastic follicles of t(14;18) containing follicular non-Hodgkin's lymphomas immunostained positively for both Bcl-2 and Mcl-1 in 24 of 27 cases. Intense immunostaining for Mcl-1 was also observed in Reed-Sternberg cells in 2 of 2 cases of Hodgkin's disease but Bcl-2 immunoreactivity was present at much lower levels. These findings demonstrate that the levels of Mcl-1 and Bcl-2 proteins are differentially regulated in normal and neoplastic cells in lymph nodes and thus suggest different roles for these proteins in the control of cell life and death in these tissues.
Bcl-2蛋白可阻止程序性细胞死亡，在许多滤泡性非霍奇金淋巴瘤中，由于涉及Bcl-2基因的t(14;18)易位，该蛋白会过度产生。Mcl-1是最近发现的一个基因，其编码的蛋白与Bcl-2有显著同源性，但其功能尚不清楚。在本研究中，我们通过免疫组织化学方法，使用特异性多克隆抗血清，比较了正常和肿瘤性淋巴结活检组织中Bcl-2和Mcl-1蛋白的体内产生模式。细胞内Mcl-1免疫反应性主要以点状模式位于细胞质中，在许多情况下也可见于核膜，这与Bcl-2的结果相似，Bcl-2位于线粒体外膜、核膜和内质网。在4例反应性扁桃体和28例有反应性滤泡增生的淋巴结中，观察到Bcl-2和Mcl-1蛋白表达的相反模式。Bcl-2免疫染色在套区淋巴细胞中最高，而大多数生发中心细胞中没有，而Mcl-1免疫反应性在生发中心淋巴细胞中最高，套区淋巴细胞中没有。Mcl-1也在一些滤泡间淋巴细胞中表达，特别是那些具有活化淋巴细胞外观的细胞。与反应性淋巴结中Bcl-2和Mcl-1的表达模式相似，2例套细胞淋巴瘤中的恶性细胞中基本没有Mcl-1蛋白，而这些细胞中发现了强烈的Bcl-2免疫染色。然而，与正常淋巴结不同的是，在27例含t(14;18)的滤泡性非霍奇金淋巴瘤的肿瘤滤泡中，有24例Bcl-2和Mcl-1免疫染色均为阳性。在2例霍奇金病患者的里德-斯腾伯格细胞中也观察到强烈的Mcl-1免疫染色，但Bcl-2免疫反应性水平要低得多。这些发现表明，Mcl-1和Bcl-2蛋白的水平在淋巴结的正常细胞和肿瘤细胞中受到不同的调节，因此提示这些蛋白在这些组织的细胞生死控制中具有不同的作用。
