HETEROGENEOUS NUCLEAR EXPRESSION OF THE PROMYELOCYTIC LEUKEMIA (PML) PROTEIN IN NORMAL AND NEOPLASTIC HUMAN TISSUES

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-typ e PML localizes in the nucleus with a typical speckled pattern that is a consequence of the concentration of the protein within discrete sub nuclear domains known as nuclear bodies. Delocalization of PML, from n uclear bodies has been documented in acute promyelocytic leukemia cell s and suggested to contribute to leukemogenesis. In an attempt to get new insights into the function of the wild-type PML; protein and to in vestigate whether it displays an altered expression pattern in neoplas ms other than acute promyelocytic leukemia, we stained a large number of normal and neoplastic human tissues with a new murine monoclonal an tibody (PG-M3) directed against the amino-terminal region of PML. As t he PG-M3 epitope is partially resistant to fixatives, only cells that overexpress PML are detected by the antibody in microwave-heated paraf fin sections, Among normal tissues, PML wets characteristically up-reg ulated in activated epithelioid histiocytes and fibroblasts in a varie ty of pathological conditions, columnar epithelium in small active thy roid follicles, wed differ entiated foamy cells in the center of sebac eous glands, and hypersecretory endometria (AriasStella), Interferons, the PML of which is a primary target gene, and estrogens are likely t o represent some of the cytokines and/or hormones that may be involved in the up-regulation of PML under these circumstances. In keeping wit h this concept, we found that PML is frequently overexpressed in Hodgk in and Reed-Sternberg cells of Hodgkin's disease, a tumor of cytokine- producing cells. Among solid tumors, overexpression of PML: was freque ntly found in carcinomas of larynx and thyroid (papillary), epithelial thymomas, and Kaposi's sarcoma, whereas carcinomas of the lung, thyro id (follicular), breast, and colon were frequently negative or weakly PML(+). We did not observe any changes in the levels of PML; expressio n as the lesion progressed from benign dysplasia to carcinoma. Our imm unohistological data are consistent with the hypothesized growth suppr essor function of PML and strongly suggest that PML; expression levels are likely to be modulated by a variety of stimuli, including cytokin es and hormones.