Gambacorta M, Flenghi L, Fagioli M, Pileri S, Leoncini L, Bigerna B, Pacini R, Tanci L N, Pasqualucci L, Ascani S, Mencarelli A, Liso A, Pelicci P G, Falini B
Institute of Pathology, Ospedale Niguarda, Milan, Italy.
Am J Pathol. 1996 Dec;149(6):2023-35.
The RING-finger promyelocytic leukemia (PML) protein is the product of the PML gene that fuses with the retinoic acid receptor-alpha gene in the t(15; 17) translocation of acute promyelocytic leukemia. Wild-type PML localizes in the nucleus with a typical speckled pattern that is a consequence of the concentration of the protein within discrete subnuclear domains known as nuclear bodies. Delocalization of PML from nuclear bodies has been documented in acute promyelocytic leukemia cells and suggested to contribute to leukemogenesis. In an attempt to get new insights into the function of the wild-type PML protein and to investigate whether it displays an altered expression pattern in neoplasms other than acute promyelocytic leukemia, we stained a large number of normal and neoplastic human tissues with a new murine monoclonal antibody (PG-M3) directed against the amino-terminal region of PML. As the PG-M3 epitope is partially resistant to fixatives, only cells that overexpress PML are detected by the antibody in microwave-heated paraffin sections. Among normal tissues, PML was characteristically up-regulated in activated epithelioid histiocytes and fibroblasts in a variety of pathological conditions, columnar epithelium in small active thyroid follicles, well differentiated foamy cells in the center of sebaceous glands, and hypersecretory endometria (Arias-Stella). Interferons, the PML of which is a primary target gene, and estrogens are likely to represent some of the cytokines and/or hormones that may be involved in the up-regulation of PML under these circumstances. In keeping with this concept, we found that PML is frequently overexpressed in Hodgkin and Reed-Sternberg cells of Hodgkin's disease, a tumor of cytokine-producing cells. Among solid tumors, overexpression of PML was frequently found in carcinomas of larynx and thyroid (papillary), epithelial thymomas, and Kaposi's sarcoma, whereas carcinomas of the lung, thyroid (follicular), breast, and colon were frequently negative or weakly PML+. We did not observe any changes in the levels of PML expression as the lesion progressed from benign dysplasia to carcinoma. Our immunohistological data are consistent with the hypothesized growth suppressor function of PML and strongly suggest that PML expression levels are likely to be modulated by a variety of stimuli, including cytokines and hormones.
环状结构域早幼粒细胞白血病（PML）蛋白是PML基因的产物，在急性早幼粒细胞白血病的t(15; 17)易位中，该基因与维甲酸受体α基因融合。野生型PML定位于细胞核，呈典型的斑点状模式，这是该蛋白在离散的核内亚结构域（称为核小体）中浓缩的结果。在急性早幼粒细胞白血病细胞中已观察到PML从核小体中脱离定位，提示这可能与白血病发生有关。为了深入了解野生型PML蛋白的功能，并研究其在急性早幼粒细胞白血病以外的肿瘤中是否表现出表达模式的改变，我们用一种针对PML氨基末端区域的新型鼠单克隆抗体（PG-M3）对大量正常和肿瘤性人类组织进行染色。由于PG-M3表位对固定剂有部分抗性，在微波加热的石蜡切片中，该抗体仅能检测到过表达PML的细胞。在正常组织中，在多种病理情况下，活化的上皮样组织细胞和成纤维细胞、小的活跃甲状腺滤泡中的柱状上皮、皮脂腺中心分化良好的泡沫细胞以及高分泌的子宫内膜（阿里亚斯-斯特拉现象）中，PML特征性地上调。干扰素（其PML是主要靶基因）和雌激素可能是在这些情况下参与PML上调的一些细胞因子和/或激素。与此概念一致，我们发现PML在霍奇金病的霍奇金和里德-斯特恩伯格细胞中经常过表达，霍奇金病是一种产生细胞因子的肿瘤。在实体瘤中，PML的过表达常见于喉癌和甲状腺癌（乳头状）以及上皮性胸腺瘤和卡波西肉瘤，而肺癌、甲状腺癌（滤泡状）、乳腺癌和结肠癌则常为阴性或PML弱阳性。随着病变从良性发育异常进展为癌，我们未观察到PML表达水平有任何变化。我们的免疫组织化学数据与PML的假定生长抑制功能一致，并强烈提示PML的表达水平可能受到多种刺激的调节，包括细胞因子和激素。
