Abstract
Multiple myeloma (MM) is an incurable B-cell malignancy. Therefore, new targets and drugs are urgently needed to improve patient outcome. Epigenetic aberrations play a crucial role in development and progression in cancer, including MM. To target these aberrations, epigenetic modulating agents, such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), are under intense investigation in solid and hematological cancers. A clinical benefit of the use of these agents as single agents and in combination regimens has been suggested based on numerous studies in pre-clinical tumor models, including MM models. The mechanisms of action are not yet fully understood but appear to involve a combination of true epigenetic changes and cytotoxic actions. In addition, the interactions with the BM niche are also affected by epigenetic modulating agents that will further determine the in vivo efficacy and thus patient outcome. A better understanding of the molecular events underlying the anti-tumor activity of the epigenetic drugs will lead to more rational drug combinations. This review focuses on the involvement of epigenetic changes in MM pathogenesis and how the use of DNMTi and HDACi affect the myeloma tumor itself and its interactions with the microenvironment.
Highlights
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the uncontrolled growth of malignant plasma cells in the bone marrow, resulting in an accumulation of monoclonal immunoglobulins (M-spike) in the blood and urine of the patient
The above interactions are mediated by secretion of multiple cytokines, including interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), IL-1, tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), Dickkopf-related protein 1 (DKK1) and secreted frizzled-related protein, that support paracrine interactions between MM cells and endothelial cells, bone marrow stromal cells (BMSC), osteoblasts, osteoclasts and immune cells
DNA methylation is the most promising to use as prognostic marker
Summary
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the uncontrolled growth of malignant plasma cells in the bone marrow, resulting in an accumulation of monoclonal immunoglobulins (M-spike) in the blood and urine of the patient. Progression of MGUS to MM and PCL is associated with additional aberrations including activating RAS mutations, deletion of. Transplantation is mostly followed by a bortezomib- or lenalidomide-based maintenance therapy The introduction of these novel agents and regimens led to an overall survival of 5–7 years in standardrisk patients [14,15,16]. Despite the promising clinical effects of the current therapies, patients eventually relapse and die of refractory disease This emphasizes the need for novel targets and treatment options. This review will focus on recent knowledge of epigenetic aberrations in MM and the use of epigenetic modulating agents, in particular histone deacetylase inhibitors (HDACi) and DNA-methyltransferase inhibitors (DNMTi) in MM
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