title: Polycomb target genes are silenced in multiple myeloma.
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.
authors.affiliation: Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala Sweden.
authors.forename: Antonia
authors.initials: A
authors.lastname: Kalushkova
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
authors.forename: Miguel
authors.initials: M
authors.lastname: Lemaire
authors.forename: Charlotte
authors.initials: C
authors.lastname: Fristedt
authors.forename: Prasoon
authors.initials: P
authors.lastname: Agarwal
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksson
authors.forename: Sarah
authors.initials: S
authors.lastname: Deleu
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Anders
authors.initials: A
authors.lastname: Osterborg
authors.forename: Kenneth
authors.initials: K
authors.lastname: Nilsson
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.forename: Fredrik
authors.initials: F
authors.lastname: Oberg
authors.forename: Helena
authors.initials: H
authors.lastname: Jernberg-Wiklund
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D019175:DNA Methylation / Q000187:drug effects; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000077767:Panobinostat; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099185:Interferon Regulatory Factor-8
chemical_list: D000241:Adenosine; D043383:Adenosylhomocysteinase; D015820:Cadherins; D054377:Chemokine CXCL12; D050989:GATA2 Transcription Factor; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D050835:Interferon Regulatory Factors; D000077767:Panobinostat; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D000099185:Interferon Regulatory Factor-8; C048460:3-deazaneplanocin; C087310:K cadherin