Epigenetic reprogramming in multiple myeloma-Challenges and opportunities

Abstract

In cancer, mutational processes act in concert with epigenetic reprogramming to endow malignant cells with hallmark properties that underpin tumorigenesis. Compared with the relatively rigid and slow processes of genetic evolution, the plastic nature of chromatin enables cells to adapt to a changing environment more rapidly. Multiple myeloma is characterised by high levels of inter- and intra-patient heterogeneity at both the genetic and epigenetic levels. Understanding the many layers of genetic and non-genetic evolution and their interplay is crucial to improve patient outcomes. In this short review, we discuss the most common and extensively characterised epigenetic alterations that occur during myeloma development. We also touch on emerging approaches to reverse the aberrant epigenome of myeloma cells as a treatment strategy.

Keywords: epigenetic drugs; epigenetics; multiple myeloma.

FIGURE 1

Common mechanisms of epigenetic regulation in multiple myeloma (MM). Left panel—t(4;14) translocation increases expression of the histone methyltransferase NSD2 (aka MMSET), altering the abundance and distribution of H3K36me2 and H3K27me3. Middle panel—Increased activity of enhancers and a more interconnected gene regulatory network in MM cells. Right panel—DNA methylation heterogeneity driven by stochastic methylation changes causes transcriptional noise and decoupling of promoter methylation and gene expression in MM cells. PC, plasma cell; TF, transcription factor.