Roy Choudhury Samrat, Ashby Cody, Zhan Fenghuang, van Rhee Frits
Pediatric Hematology-Oncology, Arkansas Children's Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Cancers (Basel). 2021 Dec 17;13(24):6348. doi: 10.3390/cancers13246348.
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; = 53) patients of major molecular subgroups, compared to age-matched healthy donors ( = 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 ≥ 0.5) between DNA methylation and expression amongst selective TRGs, such that demethylation at the promoters of and were associated to their oncogenic upregulation, while demethylation at the bodies of two key tumor suppressors 0 and 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.
高危多发性骨髓瘤（MM）患者的端粒长度（TL）维持在短临界长度范围以下，这与端粒酶的主动过表达一致。此前，DNA甲基化已被证明是端粒相关基因（TRG）表达和TL的决定因素，可用于评估不同类型癌症的风险。我们对一组新诊断的MM（NDMM；n = 53）主要分子亚组患者进行了全基因组DNA甲基化图谱分析，并与年龄匹配的健康供体（n = 4）进行了比较。结合重叠染色质标记和潜在DNA序列，分析了TRG位点的差异甲基化和表达情况。我们观察到选择性TRG之间的DNA甲基化与表达之间存在强相关性（R≥0.5），即TERT和MYC启动子处的去甲基化与其致癌性上调相关，而两个关键肿瘤抑制基因P53和RB1基因体处的去甲基化导致基因下调。我们证明TRG表达可能仅由DNA甲基化控制，或在调控区域与染色质修饰或CCCTC结合因子协同控制。此外，我们发现NDMM中TRG的低甲基化差异甲基化区域（DMR）与G-四链体形成序列稳定结合，表明这些表观遗传脆弱位点在MM发病机制中起关键作用。我们鉴定出一组五个TRG，它们在NDMM患者中存在表观遗传失调，可能作为该疾病的早期检测生物标志物或治疗靶点。
