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.
Highlights
Multiple myeloma (MM) remains a fatal hematopoietic malignancy
H3K27-tri-methylation is a common denominator for the underexpressed genes in multiple myeloma (MM)
Having established that the underexpressed gene profile in MM significantly overlaps with defined Polycomb target genes, the PRC2-mediated tri-methylation of histone H3 lysine 27 was analyzed by chromatin immunoprecipitation (ChIP) in four newly diagnosed MM patients (Figure 2A–D)
Summary
Multiple myeloma (MM) remains a fatal hematopoietic malignancy. MM is characterized by the clonal expansion of tumor cells with plasma cell features in the bone marrow and is considered a genetically heterogeneous disease [1]. In further attempts to dissect the disease phenotype, gene expression profiles have been used to refine the underlying mechanisms in molecular subsets, to discover predictors of drug response and identify novel drug targets [6,7,8,9]. It still remains unclear how MM, phenotypically representing mature plasmablasts/plasma cells, preserves the capacity of self-renewal and whether this capacity may be identified as a common gene expression signature
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