The role of epigenetics in the biology of multiple myeloma

Abstract

Several recent studies have highlighted the biological complexity of multiple myeloma (MM) that arises as a result of several disrupted cancer pathways. Apart from the central role of genetic abnormalities, epigenetic aberrations have also been shown to be important players in the development of MM, and a lot of research during the past decades has focused on the ways DNA methylation, histone modifications and noncoding RNAs contribute to the pathobiology of MM. This has led to, apart from better understanding of the disease biology, the development of epigenetic drugs, such as histone deacetylase inhibitors that are already used in clinical trials in MM with promising results. This review will present the role of epigenetic abnormalities in MM and how these can affect specific pathways, and focus on the potential of novel 'epidrugs' as future treatment modalities for MM.

Figure 1

Transcriptionally active chromatin is characterized by histone acetylation, H3K4me3 and H3K79me3 in the promoter region (which is also nucleosome depleted), allowing binding of RNA polymerase II (Pol II), as well as H4K20me1 and H3K36me3 found in the body of transcriptionally active genes. At the same time, the CpG islands of the promoter region are unmethylated, and there is DNA methylation in the gene body. Gene silencing can occur with two different mechanisms: the first one involves methylation of the CpG islands of the promoter that then allows the binding of methyl-CpG-binding protein 2 (MeCP2) and recruitment of HDACs. Notably, DNA methylation does not affect histone methylation patterns. Gene silencing by DNA methylation was previously thought to be irreversible, but there is now evidence that TET proteins can actively demethylate 5-methylcytosine (5mC) via the formation of 5hmC. The histone methyl transferase EZH2 is the catalytic component of the PRC2 that causes H3K27me3-mediated gene silencing, independently of DNA methylation.

Figure 2

The cyclin/CDK pathway. The entry in G1 phase is characterized by the assembly of CDK4/6 and cyclin D proteins, a process controlled by the INK4 family of CKIs. The cyclin D/CDK4/6 complex phosphorylates and deactivates Rb, allowing E2F to activate transcription of CDK2 and cyclins A and E that are needed for the transition to the S phase. The cyclin A/E/CDK2 complex is inhibited by the Cip/Kip family of CKIs.

Figure 3

Combination of promoter hypermethylation of tumor suppressor genes acting as inhibitors of cancer pathways as well as abnormal expression of miRNAs contribute to the activation of the cyclin D/CDK pathway, Jak/STAT3 pathway, Wnt/β-catenin signaling pathway and disruption of DAPk/p53 interaction. The dark circles above genes and miRNAs indicate DNA methylation and silencing of the respective gene/miRNA.