Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma
题目：单细胞水平解析有症状和无症状骨髓瘤的血浆细胞异质性
作者：Guy Ledergor, Assaf Weiner, […] Ido Amit
通讯作者单位：
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
发表期刊及时间：
Nature Medicine volume 24, pages1867–1876 (2018) 06 December 2018
摘要：
Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients.
多发性骨髓瘤是浆细胞恶性肿瘤，是第二常见的血癌。尽管进行了广泛的研究，但疾病异质性的特征很少，妨碍了早期诊断和改善治疗的努力。在这里，我们应用单细胞RNA测序来研究在多发性骨髓瘤进展过程中的40个个体的表达谱异质性，包括11个健康对照。从已知的多发性骨髓瘤驱动因子和其他推定因子的表达可以显示出高度的个体间变异性。我们在患有多发性骨髓瘤的29名个体中的10个发现了广泛的亚克隆结构。在早期疾病的无症状个体和治疗后残留最少的疾病患者中，我们检测到具有与活动性骨髓瘤类似的分子特征的罕见肿瘤浆细胞，可能对个性化治疗产生影响。罕见循环肿瘤细胞的单细胞分析可以精确的进行液体活检并检测反映骨髓疾病的恶性浆细胞。我们的工作建立了单细胞RNA测序，用于解剖血液恶性肿瘤，并设计有症状和无症状患者的肿瘤细胞的详细分子特征。
图表选析：
Fig. 1: Subjects with multiple myeloma display unique transcriptional signatures that converge into defined malignant pathways. 具有多发性骨髓瘤的受试者显示出独特的转录特征：聚集到确定的恶性通路中
a, tSNE plot depicting 20,568 single bone marrow plasma cells derived from 29 newly diagnosed subjects (MGUS01–07, SMM01–06, MM1–12 and AL01–04) with plasma cell neoplasms and 11 control individuals (Hip01–11). Each cluster is represented by a specific color and number (related to the heat map in Extended Data Fig. 4). b, Subjects are color-coded according to a severity gradient projected on the tSNE (gray, control; yellow, MGUS; pink, SMM; red, multiple myeloma and amyloidosis); these colors correspond to d and e. c, Index-sorting flow cytometry data represented as mean fluorescence intensity (MFI; log10 scale) for specific surface markers, projected onto the tSNE (top, CD19; bottom, CD56). d, Bar plot showing distribution of cells from subjects with multiple myeloma and control donors across the clusters (as in a). Subject are color-coded according to disease severity as in a; names above bars correspond to the individual with the majority of cells in each cluster. e, Box plots of single cell gene expression for specific genes across the 29 newly diagnosed subjects and 11 control donors (left). Each box represents 0.25–0.75 percentile of UMI count with line extension to 0.1-0.9 percentile; dot represents the mean UMI count. Subjects are color-coded according to disease severity. For each gene, corresponding histograms of bulk RNA-seq expression estimates from the CoMMpass study (TPM- transcripts per kilobase million; log scale) are shown (right). f, Map of CNAs (dark gray background) and oncogenic mutations (light gray background) depicted in black (bottom) and dendrogram of hierarchical clustering for average RNA profile of 11 participants (top) for whom targeted bulk genomic DNA sequencing data were available.
a，tSNE图描绘了来自29个新诊断具有浆细胞肿瘤的受试者（MGUS01-07，SMM01-06，MM1-12和AL01-04）其和11个对照个体（Hip01-11）的20,568个单个骨髓浆细胞。每个簇由特定颜色和数字表示（与扩展数据中的热图有关）图4。 b，受试者根据投射在tSNE上的严重性梯度进行颜色编码（灰色，对照;黄色，MGUS;粉红色，SMM;红色，多发性骨髓瘤和淀粉样变性）;这些颜色对应于d和e。 c，指数分选流式血细胞技术数据表示为投射到tSNE（顶部，CD19;底部，CD56）的特定表面标志物的平均荧光强度（MFI; log10标度）。 d，条形图显示来自具有多发性骨髓瘤的受试者和跨越所述簇的对照供体的细胞分布（如a）。受试者根据疾病严重程度进行颜色编码，如a;条形图上方的名称对应于每个聚类中具有大多数细胞的个体。 e，29个新诊断受试者和11个对照供体的特定基因的单细胞基因表达的箱形图（左）。每个框代表0.25-0.75百分位的UMI计数，线延伸至0.1-0.9百分位; dot表示平均UMI计数。受试者根据疾病严重程度进行颜色编码。对于每个基因，显示来自CoMMpass研究的大量RNA-seq表达估计的相应直方图（TPM-转录物/千碱基百万;对数标度）（右）。 f，黑色（底部）描绘的CNA（深灰色背景）和致癌突变（浅灰色背景）的图谱和11个参与者（顶部）的平均RNA谱的层次聚类的树状图，其中可获得靶向的基因组DNA测序数据。