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* Department of Experimental and Clinical Medicine "G. Salvatore", University of Catanzaro "Magna Graecia", Catanzaro, Italy;
Department of Biochemistry and Medical Biotechnology, Universita‘ degli Studi di Napoli "Federico II", Napoli, Italy;
Memorial Sloan Kettering Cancer Center, New York, NY 10065;
Department of Surgery, Department of Immunology, and Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213; and
¶ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
Early hematopoietic zinc finger/zinc finger protein 521 (EHZF/ZNF521) is a novel zinc finger protein expressed in hematopoietic stem and progenitor cells and is down-regulated during their differentiation. Its transcript is also abundant in some hematopoietic malignancies. Analysis of the changes in the antigenic profile of cells transfected with EHZF cDNA revealed up-regulation of HLA class I cell surface expression. This phenotypic change was associated with an increased level of HLA class I H chain, in absence of detectable changes in the expression of other Ag-processing machinery components. Enhanced resistance of target cells to NK cell-mediated cytotoxicity was induced by enforced expression of EHZF in the cervical carcinoma cell line HeLa and in the B lymphoblastoid cell line IM9. Preincubation of transfected cells with HLA class I Ag-specific mAb restored target cell susceptibility to NK cell-mediated lysis, indicating a specific role for HLA class I Ag up-regulation in the NK resistance induced by EHZF. A potential clinical significance of these findings is further suggested by the inverse correlation between EHZF and MHC class I expression levels, and autologous NK susceptibility of freshly explanted multiple myeloma cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Italian Association for Cancer Research, Italian Ministry for University and Research (Cluster C-04, PRIN, and Interlink) and by Public Health Service Grants R01CA110249 and P01CA113861 awarded by the National Cancer Institute, for the Department of Health and Human Services.
2 R.L. and M.F. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Ennio Carbone, University of Catanzaro "Magna Graecia", Department of Experimental & Clinical Medicine, Tumor Immunology Lab, University Campus "S. Venuta" Germaneto, Viale Europa, 88100, Catanzaro, Italy. E-mail address: ennio.carbone{at}ki.se
4 Abbreviations used in this paper: EHZF, early hematopoietic zinc finger; ALL, acute lymphoblastic leukemia; APM, Ag-processing machinery; MM, multiple myeloma; MICA, MHC class I chain-related protein A; MICB, MHC class I chain-related protein B; ULBP, UL16-binding protein; shRNA, short hairpin RNA; β2M, β2-microglobulin; MFI, mean fluorescence intensity; EGFP, enhanced GFP.
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