Epigenetic Deregulation of Telomere-Related Genes in Newly Diagnosed Multiple Myeloma Patients

SIMPLE SUMMARY: Aberrant expression of telomere-related genes (TRGs) and telomere-shortening facilitates development of different types of cancer. Given the fact that high-risk multiple myeloma (MM) patients harbor critically shortened telomeres, we investigated the epigenetic basis of TRG-expression in newly diagnosed MM patients. We demonstrated that DNA methylation alone or in cooperation with overlapping chromatin marks and underlying genomic sequence build up an epigenetic network of aberrant gene expression in TRGs. Furthermore, we identified five TRGs, which are epigenetically controlled and consistently deregulated across the major molecular subgroups of MM, identifiable at the early stage of the disease. ABSTRACT: High-risk Multiple Myeloma (MM) patients were found to maintain telomere length (TL), below the margin of short critical length, consistent with proactive overexpression of telomerase. Previously, DNA methylation has been shown as a determinant of telomere-related gene (TRG) expression and TL to assess risk in different types of cancer. We mapped genome-wide DNA methylation in a cohort of newly diagnosed MM (NDMM; n = 53) patients of major molecular subgroups, compared to age-matched healthy donors (n = 4). Differential methylation and expression at TRG-loci were analyzed in combination with overlapping chromatin marks and underlying DNA-sequences. We observed a strong correlation (R(2) ≥ 0.5) between DNA methylation and expression amongst selective TRGs, such that demethylation at the promoters of DDX1 and TERF1 were associated to their oncogenic upregulation, while demethylation at the bodies of two key tumor suppressors ZNF208 and RAP1A led to downregulation of the genes. We demonstrated that TRG expression may be controlled by DNA methylation alone or in cooperation with chromatin modifications or CCCTC-binding factor at the regulatory regions. Additionally, we showed that hypomethylated DMRs of TRGs in NDMM are stabilized with G-quadruplex forming sequences, suggesting a crucial role of these epigenetically vulnerable loci in MM pathogenesis. We have identified a panel of five TRGs, which are epigenetically deregulated in NDMM patients and may serve as early detection biomarkers or therapeutic targets in the disease.