lunes, 19 de julio de 2010

Polycomb Target Genes Are Silenced in Multiple Myeloma

Polycomb Target Genes Are Silenced in Multiple Myeloma

Antonia Kalushkova1#, Mårten Fryknäs1#, Miguel Lemaire2, Charlotte Fristedt1, Prasoon Agarwal1, Maria Eriksson1, Sarah Deleu2, Peter Atadja3, Anders Österborg4, Kenneth Nilsson1, Karin Vanderkerken2, Fredrik Öberg1, Helena Jernberg-Wiklund1*

1 Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala Sweden, 2 Department Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium, 3 Novartis Institute for Biomedical Research, Cambridge, Massachusetts, United States of America, 4 Department of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden

Abstract
Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.

Citation: Kalushkova A, Fryknäs M, Lemaire M, Fristedt C, Agarwal P, et al. (2010) Polycomb Target Genes Are Silenced in Multiple Myeloma. PLoS ONE 5(7): e11483. doi:10.1371/journal.pone.0011483

Editor: Axel Imhof, Ludwig-Maximilians-Universität München, Germany


Received: February 24, 2010; Accepted: June 2, 2010; Published: July 9, 2010

Copyright: © 2010 Kalushkova et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by grants from The Swedish Cancer Society, The Swedish Research Council, The Multiple Myeloma Research Foundation, VonKantzows stiftelse, Stichting tegen Kanker, FWO-Vlaanderen and GOA-Vrije Universiteit Brussel. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: Helena.Jernberg_Wiklund@genpat.uu.se

# These authors contributed equally to this work.

open here to see the full-text:
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0011483

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