Role of epigenetics-microRNA axis in drug resistance of multiple myeloma

Abstract

Despite administration of novel therapies, multiple myeloma (MM) remains incurable with resistance to drugs leading to relapse in most patients. Thus, it is critical to understand the detailed mechanisms underlying the drug resistance of MM and develop more effective therapeutic strategies. Genetic abnormalities are well known to play a central role in MM pathogenesis and therapy resistance; however, epigenetic aberrations mainly affecting the patterns of DNA methylation/histone modifications of genes (especially tumor suppressors) and miRNAs have also been shown to be involved. Importantly, while epigenetic silencing of miRNAs in MM is well documented, some epigenetic markers are known to be direct targets of miRNAs particularly the recently described “epimiRNAs”. Drugs targeting epigenetic modifiers (e.g., HDACs, EZH2) can sensitize MM-resistant cells to anti-myeloma drugs and reversibility of epigenetic changes makes these drugs promising therapeutic agents. Therefore, combination of miRNA mimics with inhibitors of epigenetic modifiers would be a more potent therapeutic strategy in MM patients in relapse or refractory to treatments. In this review, we will discuss the findings of recent investigations on epigenetics/miRNA regulatory axis in development of drug resistance in MM and highlight possible approaches for therapeutic applications of such interaction.

RETRACTED: miR‐125a suppresses malignancy of multiple myeloma by reducing the deubiquitinase USP5

“…miRNA plays a role in regulating gene transcription by inhibiting or degrading target mRNA. 34,35 miRNA-125 is a kind of miRNA involved in tumorigenesis and development, including miR-125a, miR-125b-1, and miR-125b-2, and has the effect of oncogene or tumor-suppressor gene. 32,33 In addition, it has been found that the abnormal expression of miRNA may be associated to the proliferation, F I G U R E 3 Identification of USP5 as the target gene of miR-125a in MM cells.…”

Validation of multiple myeloma risk stratification indices in routine clinical practice: Analysis of data from the Czech Myeloma Group Registry of Monoclonal Gammopathies

“…Much of the clinical heterogeneity of MM is thought to arise from multiple genomic events that result in tumor development and progression 2. These include genetic and epigenetic alterations, including point mutations, translocations (eg, t(4;14) and t(14;16)), deletions (eg, del(17p)),3 aberrant DNA and histone methylation,4 and/or abnormal microRNA expression 5…”

The role of long non‐coding RNAs in multiple myeloma

“…Zhan et al found that KIAA0495, an lncRNA transcribed from chromosome 1p36, was progressively downregulated from normal plasma cells to monoclonal gammopathy of undetermined significance (MGUS) and to symptomatic myeloma by gene expression profiling . DNA methylation has been implicated in the pathogenesis and prognosis of MM . However, the methylation of KIAA0495, which leads to the reversible silencing of KIAA0495 expression in MM, has been rarely detected in primary samples of MM at diagnosis or relapse.…”

“…38 DNA methylation has been implicated in the pathogenesis and prognosis of MM. 39 However, the methylation of KIAA0495, which leads to the reversible silencing of KIAA0495 expression in MM, has been rarely detected in primary samples of MM at diagnosis or relapse. This means that it may not be associated with its progressive downregulation in cells from normal plasma cells to MGUS and to MM.…”