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Epigenetic silencing of the tetraspanin CD9 during disease progression in multiple myeloma cells and correlation with survival.

De Bruyne, Elke and Bos, Tomas Jan and Asosingh, Kewal and Vande Broek, Isabelle and Menu, Eline and Van Valckenborgh, Els and Atadja, Peter and Coiteux, Valérie and Leleu, Xavier and Thielemans, Kris and Van Camp, Ben and Vanderkerken, Karin and Van Riet, Ivan (2008) Epigenetic silencing of the tetraspanin CD9 during disease progression in multiple myeloma cells and correlation with survival. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 14 (10). pp. 2918-2926. ISSN 1078-0432

Abstract

PURPOSE: The purpose of this study was to investigate expression and epigenetic regulation of CD9 in multiple myeloma (MM) cells during disease progression. EXPERIMENTAL DESIGN: CD9 expression was retrospectively analyzed on bone marrow myeloma samples from 81 patients by immunophenotyping. CD9 expression by murine 5TMM cells was detected by flow cytometric staining and quantitative PCR. The methylation status of the CD9 promoter was determined by bisulfite PCR sequencing. RESULTS: Primary plasma cells in the majority of MM patients with nonactive disease (n = 28) showed CD9 expression, whereas most cases with active disease (n = 53) were CD9 negative. CD9 expression in diagnostic bone marrow samples (n = 74) correlated with survival. Moreover, CD9 expression on murine 5T33 and 5T2MM cells was significantly down-regulated during disease development. Treatment of CD9-nonexpressing 5T33MMvt cells with the clinically relevant histone deacetylase inhibitor LBH589 resulted in a significant increase in CD9 expression. In contrast, cells treated with the demethylation agent 5-aza-2'deoxycytidine barely showed any increase. A combination study with both compounds resulted in a strong synergistic reactivation of CD9. CD9-expressing 5T33MMvv cells and 5T33MMvt cells stably transduced with a mCD9 lentiviral transferplasmid were shown to be more susceptible to natural killer cell-mediated cytolysis than CD9-negative 5T33MMvt cells. CONCLUSIONS: CD9 expression correlates with disease status and survival of MM patients. In the murine 5T33MM model, we show that histone modifications, and to a lesser extent CpG methylation, are key epigenetic events in CD9 down-regulation. Furthermore, as CD9 expression becomes down-regulated, 5T33MM cells become less susceptible to natural killer cell-mediated cytolysis.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution
Keywords: multiple myeloma; CD9; epigenetic silencing; bisulfite sequencing; lentiviral transduction
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Date Deposited: 14 Dec 2009 13:48
Last Modified: 31 Jan 2013 00:52
URI: https://oak.novartis.com/id/eprint/1648

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