Purpose: In multiple myeloma (MM), therapy-induced clonal evolution is associated with treatment resistance and is one of the most important hindrances toward a cure for MM. To further understand the molecular mechanisms controlling the clonal evolution of MM, we applied single-cell RNA-sequencing (scRNA-seq) to paired diagnostic and post-treatment bone marrow (BM) samples. Experimental Design: scRNA-seq was performed on 38 BM samples from patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 1), MM patients at diagnosis (n = 19), MM post-treatment (n = 17), and one healthy donor. The single-cell transcriptome data of malignant plasma cells and the surrounding immune microenvironment were analyzed. Results: Profiling by scRNA-seq data revealed three primary trajectories of transcriptional evolution after treatment: clonal elimination in patients with undetectable minimal residual disease (MRD-), as well as clonal stabilization and clonal selection in detectable MRD (MRD+) patients. We noted a metabolic shift towards fatty acid oxidation in cycling-resistant plasma cells (PCs), while selective PCs favored the NF-κB pathway. Intriguingly, when comparing the genetic and transcriptional dynamics, we found a significant correlation between genetic and non-genetic factors in driving the clonal evolution. Furthermore, we identified variations in cellular interactions between malignant plasma cells and the tumor microenvironment (TME). Selective PCs showed the most robust cellular interactions with the TME. Conclusions: These data suggest that MM cells could rapidly adapt to induction treatment through transcriptional adaptation, metabolic adaptation, and specialized immune evasion. Targeting therapy-induced resistance mechanisms may help to avert refractory disease in multiple myeloma.

中文翻译：

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通过单细胞测序鉴定多发性骨髓瘤最小残留克隆中治疗诱导的克隆进化和耐药途径


目的：在多发性骨髓瘤 (MM) 中，治疗诱导的克隆进化与治疗耐药性相关，是治愈 MM 的最重要障碍之一。为了进一步了解控制 MM 克隆进化的分子机制，我们将单细胞 RNA 测序 (scRNA-seq) 应用于配对的诊断和治疗后骨髓 (BM) 样本。实验设计：对 38 份 BM 样本进行了 scRNA-seq，这些样本来自意义未定的单克隆丙种球蛋白病 (MGUS) 患者 (n = 1)、诊断时的 MM 患者 (n = 19)、治疗后的 MM 患者 (n = 17) 和一名健康的捐赠者。分析恶性浆细胞及其周围免疫微环境的单细胞转录组数据。结果：通过 scRNA-seq 数据分析揭示了治疗后转录进化的三个主要轨迹：不可检测的微小残留病 (MRD-) 患者的克隆消除，以及可检测的 MRD (MRD+) 患者的克隆稳定和克隆选择。我们注意到循环抗性浆细胞 (PC) 中向脂肪酸氧化的代谢转变，而选择性 PC 有利于 NF-κB 途径。有趣的是，在比较遗传和转录动力学时，我们发现遗传和非遗传因素在驱动克隆进化方面存在显着相关性。此外，我们还发现了恶性浆细胞和肿瘤微环境（TME）之间细胞相互作用的变化。选择性 PC 显示出与 TME 最强大的细胞相互作用。结论：这些数据表明，MM 细胞可以通过转录适应、代谢适应和专门的免疫逃避来快速适应诱导治疗。 针对治疗引起的耐药机制可能有助于避免多发性骨髓瘤的难治性疾病。