Polycomb target genes are silenced in multiple myeloma

• Published in: PloS one Vol. 5; no. 7; p. e11483
• Main Authors: Kalushkova, Antonia, Fryknäs, Mårten, Lemaire, Miguel, Fristedt, Charlotte, Agarwal, Prasoon, Eriksson, Maria, Deleu, Sarah, Atadja, Peter, Osterborg, Anders, Nilsson, Kenneth, Vanderkerken, Karin, Oberg, Fredrik, Jernberg-Wiklund, Helena
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.07.2010; Public Library of Science (PLoS)
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Adenosine - therapeutic use; Adenosylhomocysteinase - antagonists & inhibitors; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biotechnology; Blotting, Western; Cadherins - genetics; Cadherins - metabolism; Cancer genetics; Cell Line, Tumor; Cells, Cultured; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Chromatin; Chromatin Immunoprecipitation; Comparative analysis; Computational Biology; Dermatologi och venerologi, klinisk genetik, invärtesmedicin; Dermatology and venerology,clinical genetics, internal medicine; Development and progression; DNA methylation; DNA Methylation - drug effects; Drug therapy; Embryo fibroblasts; Embryos; Fibroblasts; GATA2 Transcription Factor - genetics; GATA2 Transcription Factor - metabolism; Gene expression; Gene silencing; Genes; Genetic aspects; Genetic engineering; Genetics and Genomics/Epigenetics; Genomics; Haematology; Hematologi; Hematology/Myeloma; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Humans; Hydrolase; Hydroxamic Acids - pharmacology; Hydroxamic Acids - therapeutic use; Immunoprecipitation; Indoles; Inhibitors; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Internal medicine; Invärtesmedicin; Kaplan-Meier Estimate; Kinases; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Methylation; Mice; Molecular Biology/Histone Modification; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - mortality; Panobinostat; Pharmacology; Plasma; Plasma cells; Polycomb group proteins; Proteins; Repressor Proteins - genetics; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Stem cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0011483

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.