Kamyar Bagheri - Student Research Committee, Abadan University Of Medical Sciences, Abadan, Iran
Mohammad Reza Askari - Student Research Committee, Abadan University Of Medical Sciences, Abadan, Iran
Ardalan Salehi - Student Research Committee, Abadan University Of Medical Sciences, Abadan, Iran
Samaneh Abbasi - Department of Microbiology, School of Medicine, Abadan University of Medical Sciences, Abadan, Iran

Multiple myeloma (MM) is a complex and often aggressive malignancy of plasma cells, which are a type of white blood cell responsible for producing antibodies. Advances in genetics and epigenetics have significantly enhanced our understanding of the molecular mechanisms underlying this disease, leading to improved diagnostic techniques and the development of targeted therapies. In multiple myeloma there are genetic abnormalities that drive the proliferation and survival of malignant plasma cells. These abnormalities include chromosomal translocations, deletions, amplifications, and point mutations. One of the most common genetic events in MM is the translocation involving the immunoglobulin heavy chain (IgH) locus on chromosome ۱۴, which can juxtapose this locus with various oncogenes such as FGFR۳, CCND۱, and MAF, leading to their overexpression and subsequent cell proliferation. Beyond genetic mutations, epigenetic modifications are pivotal in MM development and progression. Epigenetics refers to heritable changes in gene expression that do not involve alterations in the DNA sequence itself. These changes include DNA methylation, histone modification, and non-coding RNA regulation. In MM, abnormal DNA methylation patterns are common and can lead to the silencing of tumor suppressor genes or activation of oncogenes. For instance, hypermethylation of the promoter regions of genes such as p۱۶INK۴a, a cell cycle inhibitor, results in their downregulation and unchecked cell proliferation. Histone modifications, such as acetylation and methylation, also play a crucial role. In MM, deregulation of histone deacetylases (HDACs) and histone methyltransferases (HMTs) alters chromatin structure and gene expression. For example, overexpression of EZH۲, a histone methyltransferase, leads to the silencing of genes involved in apoptosis and differentiation, promoting MM cell survival. Non-coding RNAs, particularly microRNAs (miRNAs), further contribute to MM pathogenesis. Dysregulation of miRNAs can result in aberrant gene expression. For instance, overexpression of miR-۲۱ and miR-۲۲۱/۲۲۲ can suppress tumor suppressor genes and enhance oncogenic pathways, facilitating MM progression. The understanding of genetic and epigenetic mechanisms in MM has led to the development of novel diagnostic tools. Techniques such as next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) allow for the detection of specific genetic abnormalities and mutations, providing insights into the disease prognosis and guiding treatment decisions. In terms of therapy, targeted treatments have revolutionized MM management. Proteasome inhibitors like bortezomib exploit the high protein turnover in MM cells, leading to apoptosis. Immunomodulatory drugs (IMiDs) such as lenalidomide enhance immune responses against MM cells and inhibit angiogenesis. HDAC inhibitors, such as vorinostat and panobinostat, modify the acetylation status of histones, leading to re-expression of silenced tumor suppressor genes and induction of apoptosis. DNA methyltransferase inhibitors (DNMTis), although primarily used in other hematologic malignancies, are being explored in MM to reverse aberrant DNA methylation patterns. In conclusion, the interplay of genetic and epigenetic factors in multiple myeloma underscores the complexity of this disease. Continued exploration of these molecular mechanisms will not only enhance diagnostic precision but also pave the way for innovative and more effective therapeutic strategies, ultimately improving outcomes for patients with MM.

Multiple Myeloma, Genetics, Epigenetics, Molecular mechanisms, Molecular diagnostics