Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA.
Nat Commun. 2021 May 7;12(1):2559. doi: 10.1038/s41467-021-22804-x.
Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect "B cell-featured" plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options.
多发性骨髓瘤(MM)的特征是浆细胞的不受控制的增殖。尽管最近的治疗进展,但由于疾病进展尚不完全清楚,因此仍然无法治愈。为了研究 MM 及其免疫环境,我们应用单细胞 RNA 和连锁读取全基因组测序对 14 名患者的不同疾病阶段的 29 个纵向样本进行了分析。在这里,我们收集了 17267 个浆细胞和 57719 个免疫细胞,发现了患者特异性的浆细胞谱和免疫细胞表达变化。具有相同遗传改变的患者倾向于使浆细胞和免疫细胞聚类在一起。通过整合批量基因组学和单细胞图谱,我们跟踪浆细胞亚群在疾病阶段的变化,并发现了三种模式:稳定性(从癌前到诊断),获得或丢失(从诊断到复发)。在多个患者中,我们检测到与 B 细胞密切聚类的“B 细胞特征”浆细胞亚群,暗示其起源细胞。我们使用 CyTOF 基于蛋白质的测定法验证了浆细胞亚群中 AP-1 复合物的差异表达(JUN 和 FOS),单细胞 RNA 和 CyTOF 数据的综合分析揭示了潜在的导致炎症调节的 AP-1 下游靶标(IL6 和 IL1B)。我们的工作代表了 MM 进展过程中肿瘤和微环境的纵向研究,为扩大治疗选择铺平了道路。