Abstract
Simple SummaryAberrant 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.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 (R2 ≥ 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.
Highlights
Multiple Myeloma (MM) is a B-cell neoplasm, manifested with abnormal infiltration of plasma cells (PCs) in the bone marrow matrix, which leads to the development of lytic bone lesions and myelosuppression [1]
Selective telomere-related gene (TRG) Are Differentially Expressed in newly diagnosed MM (NDMM)
We aimed to evaluate the impact of 70 known TRGs in MM and observed a subgroup-specific differential expression pattern among the NDMM subgroups
Summary
Multiple Myeloma (MM) is a B-cell neoplasm, manifested with abnormal infiltration of plasma cells (PCs) in the bone marrow matrix, which leads to the development of lytic bone lesions and myelosuppression [1]. In addition to etiological genetic and epigenetic features, telomere length (TL) has been identified as a crucial determinant of survival in patients with MM. Patients with MM harboring high telomerase activity and short TL were marked as a ‘high-risk’ group, having significantly (p < 0.0001; hazard ratio = 3.4) shorter overall survival [14,15]. An increased number of telomere aggregates were ascribed as a prognostic biomarker for high-risk in the smoldering multiple myeloma (SMM) patients, consistent with their poor drug susceptibility and short-term survival [17]. While TL maintenance is found to be crucially linked to the prognosis and survival of the disease, both long- and short-term inhibition of telomerase resulted in reduced growth of MM cells [18,19]
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