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

Abstract

Multiple Myeloma (MM) is a malignancy of plasma cells infiltrating the bone marrow (BM). Many studies have demonstrated the crucial involvement of bone marrow stromal cells in MM progression and drug resistance. Together with the BM microenvironment (BMME), epigenetics also plays a crucial role in MM development. A variety of epigenetic regulators, including histone acetyltransferases (HATs), histone methyltransferases (HMTs) and lysine demethylases (KDMs), are altered in MM, contributing to the disease progression and prognosis. In addition to histone modifications, DNA methylation also plays a crucial role. Among others, aberrant epigenetics involves processes associated with the BMME, like bone homeostasis, ECM remodeling or the development of treatment resistance. In this review, we will highlight the importance of the interplay of MM cells with the BMME in the development of treatment resistance. Additionally, we will focus on the epigenetic aberrations in MM and their role in disease evolution, interaction with the BMME, disease progression and development of drug resistance. We will also briefly touch on the epigenetic treatments currently available or currently under investigation to overcome BMME-driven treatment resistance.

Epigenetic Crosstalk between Malignant Plasma Cells and the Tumour Microenvironment in Multiple Myeloma

“…Targeting the epigenome to block the relationships between MM plasma cells and the BMME might still be a productive approach in the future. If the therapeutical objective is not a direct action on the MM plasma cells but, instead, an attempt to modify the BMME’s influence, the use of low dosages of epigenetic drugs combined with the dispensation of traditional anti-MM substances might be able to inhibit the microenvironment-caused pro-tumoural effects and decrease MM-correlated events with tolerable toxicities [ 153 ].…”

Multiple Myeloma: Challenges Encountered and Future Options for Better Treatment

“…A better understanding of histone modifications, such as deacetylation and methylation, could also be useful in combating drug resistance. Although many dysregulations of the epigenome in MM have been studied by researchers, only one epigenetic treatment for MM has been approved to date [137]. Pan-histone deacetylase (HDAC) inhibitor panobinostat is the only epigenetic drug that has been used to date [137].…”

“…Although many dysregulations of the epigenome in MM have been studied by researchers, only one epigenetic treatment for MM has been approved to date [137]. Pan-histone deacetylase (HDAC) inhibitor panobinostat is the only epigenetic drug that has been used to date [137]. This drug interferes with the chaperone function of HSP90 and leads to the suppression of tumor growth [138].…”

“…HDAC inhibitors have multiple modes of action, hence they could be useful in many drug resistance cases. HDACs alter histones and DNA, and also affect the post-transcriptional modifications of other proteins, which could perhaps act as an important epigenetic modifier [137]. Epigenetic inhibitors with a combination of miRNAs could be effectively used for drug resistant cases.…”

The capacity of stem cells in treatment of diabetes

“…Bone marrow stromal stem cells: In fact, they are non-hematopoietic cells that can be found in the bone marrow and are called mesenchymal stem cells. Mesenchymal stem cells are multipotent stem cells that can differentiate into various types of cells in both laboratory environments and body environments [30]. In addition to bone marrow, there are other sources known as tissue-specific mesenchymal stem cells which are used for obtaining mesenchymal stem cells.…”