Lynnsey McLain

 Introduction. Multiple myeloma is a malignancy of plasma cells in the bone marrow, resulting in the excessive production of non-functional immunoglobulins.¹ The incidence of multiple myeloma in the US is approximately 4 per 100,000 people, which accounts for more than 10% of all hematological malignancies and 1% of all cancers.² The etiology of multiple myeloma can be attributed to chromosomal abnormalities, disruptions in the bone marrow microenvironment, and various epigenetic mechanisms, including DNA methylation. Epigenetic alterations are especially important in the mechanisms of drug resistance, immune regulation and disease progression of multiple myeloma.¹  Methods. Variations in DNA methylation patterns were mapped using median methylation levels of differentially methylated regions from newly diagnosed multiple myeloma patients and this data was compared to samples of healthy donors. DMAP was used for DNA methylation analysis.³ Gene ontology analysis was used to identify differential methylation patterns and gene expression. CM-272, a DNMT inhibitor, was used to reactivate hypermethylated/silenced genes of myeloma mesenchymal stem cells in vitro.⁴ In addition, the DNA methylation levels of HLA-G were assessed via peptide analysis and compared to expression levels of DNMT.⁵  Results. 40% of variations in gene expression in multiple myeloma were attributed to DNA methylation. t(4;14), a translocation found in 15-20% of multiple myeloma cases and correlated to a poorer prognosis, was linked to DNA methylation events responsible for the mutation of 18 oncogenic genes, including those involved in mTOR, PI3K-AKT and MAPK signaling pathways. Hypermethylation events in t(11;14) were found to cause mutation in genes involved in JAK-STAT signaling, focal adhesion and cell cycle pathways.³ The Homeobox family of genes, specifically Hox genes, had the most significant DNA methylation profiles, corresponding to the different stages of multiple myeloma. Inhibition of DNMTs restored the differentiation of mesenchymal stem cells and reduced tumor burden in mice models.⁴ Decreased expression of DNMTs decreased methylation events and increased transcription of HLA-G.⁵ Conclusions. t(11;14) and t(4;14) are genetic origins of aberrant DNA methylation patterns in multiple myeloma. Varying methylation patterns in different stages of multiple myeloma link DNMTs and the differentiation of mesenchymal stem cells to cancer progression. HLA-G promotes a mechanism of immune avoidance by multiple myeloma cells, by inhibiting NK cell activity and T cell mediated lysis. By preventing and reversing numerous mechanisms of multiple myeloma progression, drug resistance and immune regulation, DNA methylation inhibitors present as a promising treatment for multiple myeloma.

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3. Choudhury SR, Ashby C, Tytarenko R, et al. The functional epigenetic landscape of aberrant gene expression in molecular subgroups of newly diagnosed multiple myeloma. J Hematol Oncol. Aug 6 2020;13(1):108. doi:10.1186/s13045-020-00933-y
4. Garcia-Gomez A, Li T, de la Calle-Fabregat C, et al. Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease. Nat Commun. Jan 18 2021;12(1):421. doi:10.1038/s41467-020-20715-x
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