The functional epigenetic landscape of aberrant gene expression in molecular subgroups of newly diagnosed multiple myeloma

J Hematol Oncol. 2020 Aug 6;13(1):108. doi: 10.1186/s13045-020-00933-y.


Background: Multiple Myeloma (MM) is a hematological malignancy with genomic heterogeneity and poor survival outcome. Apart from the central role of genetic lesions, epigenetic anomalies have been identified as drivers in the development of the disease.

Methods: Alterations in the DNA methylome were mapped in 52 newly diagnosed MM (NDMM) patients of six molecular subgroups and matched with loci-specific chromatin marks to define their impact on gene expression. Differential DNA methylation analysis was performed using DMAP with a ≥10% increase (hypermethylation) or decrease (hypomethylation) in NDMM subgroups, compared to control samples, considered significant for all the subsequent analyses with p<0.05 after adjusting for a false discovery rate.

Results: We identified differentially methylated regions (DMRs) within the etiological cytogenetic subgroups of myeloma, compared to control plasma cells. Using gene expression data we identified genes that are dysregulated and correlate with DNA methylation levels, indicating a role for DNA methylation in their transcriptional control. We demonstrated that 70% of DMRs in the MM epigenome were hypomethylated and overlapped with repressive H3K27me3. In contrast, differentially expressed genes containing hypermethylated DMRs within the gene body or hypomethylated DMRs at the promoters overlapped with H3K4me1, H3K4me3, or H3K36me3 marks. Additionally, enrichment of BRD4 or MED1 at the H3K27ac enriched DMRs functioned as super-enhancers (SE), controlling the overexpression of genes or gene-cassettes.

Conclusions: Therefore, this study presents the underlying epigenetic regulatory networks of gene expression dysregulation in NDMM patients and identifies potential targets for future therapies.

Keywords: DNA methylation; epigenetics; gene regulation; myeloma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneuploidy
  • Chromosomes, Human, Pair 11 / genetics
  • Chromosomes, Human, Pair 11 / ultrastructure
  • Chromosomes, Human, Pair 14 / genetics
  • Chromosomes, Human, Pair 14 / ultrastructure
  • Chromosomes, Human, Pair 4 / genetics
  • Chromosomes, Human, Pair 4 / ultrastructure
  • Cyclin D1 / biosynthesis
  • Cyclin D1 / genetics
  • Cyclin D2 / biosynthesis
  • Cyclin D2 / genetics
  • DNA Methylation
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism
  • Epigenesis, Genetic*
  • Epigenome*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Gene Ontology
  • Gene Regulatory Networks / genetics*
  • Histone Code
  • Histones / metabolism
  • Humans
  • Multiple Myeloma / classification
  • Multiple Myeloma / genetics*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Plasma Cells / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-maf / genetics
  • Translocation, Genetic


  • CCND1 protein, human
  • CCND2 protein, human
  • Cyclin D2
  • DNA, Neoplasm
  • Histones
  • MAF protein, human
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-maf
  • Cyclin D1