Department of Biological Hematology, CHU Montpellier, Montpellier, France.
Institute of Human Genetics, UMR 9002 CNRS-UM, Montpellier, France.
Theranostics. 2022 Jan 16;12(4):1715-1729. doi: 10.7150/thno.54453. eCollection 2022.
Human multiple myeloma (MM) cell lines (HMCLs) have been widely used to understand the molecular processes that drive MM biology. Epigenetic modifications are involved in MM development, progression, and drug resistance. A comprehensive characterization of the epigenetic landscape of MM would advance our understanding of MM pathophysiology and may attempt to identify new therapeutic targets. We performed chromatin immunoprecipitation sequencing to analyze histone mark changes (H3K4me1, H3K4me3, H3K9me3, H3K27ac, H3K27me3 and H3K36me3) on 16 HMCLs. Differential analysis of histone modification profiles highlighted links between histone modifications and cytogenetic abnormalities or recurrent mutations. Using histone modifications associated to enhancer regions, we identified super-enhancers (SE) associated with genes involved in MM biology. We also identified promoters of genes enriched in H3K9me3 and H3K27me3 repressive marks associated to potential tumor suppressor functions. The prognostic value of genes associated with repressive domains and SE was used to build two distinct scores identifying high-risk MM patients in two independent cohorts (CoMMpass cohort; n = 674 and Montpellier cohort; n = 69). Finally, we explored H3K4me3 marks comparing drug-resistant and -sensitive HMCLs to identify regions involved in drug resistance. From these data, we developed epigenetic biomarkers based on the H3K4me3 modification predicting MM cell response to lenalidomide and histone deacetylase inhibitors (HDACi). The epigenetic landscape of MM cells represents a unique resource for future biological studies. Furthermore, risk-scores based on SE and repressive regions together with epigenetic biomarkers of drug response could represent new tools for precision medicine in MM.
人多发性骨髓瘤（MM）细胞系（HMCL）已被广泛用于了解驱动 MM 生物学的分子过程。表观遗传修饰参与 MM 的发生、进展和耐药。对 MM 的表观基因组进行全面表征将有助于我们理解 MM 的病理生理学，并可能试图确定新的治疗靶点。我们进行了染色质免疫沉淀测序，以分析 16 种 HMCL 中组蛋白标记变化（H3K4me1、H3K4me3、H3K9me3、H3K27ac、H3K27me3 和 H3K36me3）。组蛋白修饰谱的差异分析突出了组蛋白修饰与细胞遗传学异常或反复突变之间的联系。使用与增强子区域相关的组蛋白修饰，我们确定了与 MM 生物学相关的超级增强子（SE）。我们还确定了富含 H3K9me3 和 H3K27me3 抑制标记的基因启动子，这些基因与潜在的肿瘤抑制功能相关。与抑制性结构域和 SE 相关的基因的预后价值被用于在两个独立队列（CoMMpass 队列；n=674 和 Montpellier 队列；n=69）中构建两个不同的评分，以识别高危 MM 患者。最后，我们比较了耐药和敏感的 HMCL 中的 H3K4me3 标记，以鉴定与耐药相关的区域。从这些数据中，我们基于 H3K4me3 修饰开发了预测 MM 细胞对来那度胺和组蛋白去乙酰化酶抑制剂（HDACi）反应的表观遗传生物标志物。MM 细胞的表观基因组代表了未来生物学研究的独特资源。此外，基于 SE 和抑制性区域的风险评分以及药物反应的表观遗传生物标志物可能代表 MM 精准医学的新工具。
