Epigenetic Aberrations in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by proliferation of clonal plasma cells within the bone marrow. Several advances in defining key processes responsible for MM pathogenesis and disease progression have been made; and dysregulation of epigenetics, including DNA methylation and histone modification, has emerged as a crucial regulator of MM pathogenesis. In the present review article, we will focus on the role of epigenetic modifications within the specific context of MM.

Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

“…Around 10–15% of MM patients harbor the t(4;14)(p16;q32) translocation that results in overexpression of the receptor tyrosine kinase FGFR3 and the histone methyltransferase MMSET [ 1 , 2 ]. Although overexpression of MMSET is universal in t(4;14) [ 199 ], approximately 30% of t(4;14) patients is FGFR3 negative [ 4 , 5 ].…”

“…Despite recent clinical improvements due to the development of novel drugs, the outcome for MM patients remains dismal. The stepwise malignant transformation of plasma cells leading up to MM is accompanied by genetic and epigenetic changes that have been well studied over the recent years (reviewed in [ 1 , 2 , 3 , 4 ]). Additionally, it is becoming increasingly evident that cancer cells display altered metabolic features related to increased demands and rewired regulation of metabolic genes, often caused by oncogene activation.…”

Relapsed/Refractory Multiple Myeloma in 2020/2021 and Beyond

“…CNA acquisition also differs between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 vs. CCND1 tumors [84]. Importantly, epigenetic aberrations including DNA methylation, histone modification, non-coding RNA and super-enhancers are increasingly recognized to play a key role in MM pathogenesis, the clonal heterogeneity and plasticity of MM in its microenvironment, in particular [85,86]. Most recently, primary molecular events involving SMARC2, NSD2, and PTP4A3 have been identified to affect key epigenetic enzymes, i.e., MMSET [87].…”

Investigating the Interplay between Myeloma Cells and Bone Marrow Stromal Cells in the Development of Drug Resistance: Dissecting the Role of Epigenetic Modifications

“…These BRD-containing proteins initiate the recruitment of transcriptional activators, positively regulating gene expressions [99]. One of these activators, NSD3, has been shown to act on the chromatin microenvironment at BRD4 target genes, thereby altering the gene transcription and favoring MM pathogenesis [100]. The specific targeting of BRD-containing proteins has an antimyeloma effect.…”