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

SIMPLE SUMMARY: Despite advances made in the last two decades, multiple myeloma (MM) is still an incurable disease. The genetic complexity of MM and the presence of intra-clonal heterogeneity are major contributors to disease relapse and the development of treatment resistance. Additionally, the bone marrow microenvironment is known to play a pivotal role in MM disease progression. Together with genetic modifications, epigenetic changes have been shown to influence MM development and progression. However, epigenetic treatments for MM are still lacking. This is mainly due to the high rate of adverse events of epigenetic drugs in clinical practice. In this review, we will focus on the role of epigenetic modifications in MM disease progression and the development of drug resistance, as well as their role in shaping the interplay between bone marrow stromal cells and MM cells. The current and future treatment strategies involving epigenetic drugs will also be addressed. 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.