Dana-Farber Cancer Institute, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Boston, Massachusetts, USA.
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
JCI Insight. 2023 Feb 8;8(3):e159924. doi: 10.1172/jci.insight.159924.
To better characterize the heterogeneity of multiple myeloma (MM), we profiled plasma cells (PCs) and their B cell lymphopoiesis in the BM samples from patients with monoclonal gammopathy of undetermined significance, smoldering MM, and active MM by mass cytometry (CyTOF) analysis. Characterization of intra- and interneoplastic heterogeneity of malignant plasmablasts and PCs revealed overexpression of the MM SET domain (MMSET), Notch-1, and CD47. Variations in upregulation of B cell signaling regulators (IFN regulatory factor 4 [IRF-4], CXCR4, B cell lymphoma 6 [Bcl-6], c-Myc, myeloid differentiation primary response protein 88 [MYD88], and spliced X box-binding protein 1 [sXBP-1]) and aberrant markers (CD319, CD269, CD200, CD117, CD56, and CD28) were associated with different clinical outcomes in clonal PC subsets. In addition, prognosis was related to heterogeneity in subclonal expression of stemness markers, including neuroepithelial stem cell protein (Nestin), SRY-box transcription factor 2 (Sox2), Krüppel-like factor 4 (KLF-4), and Nanog. Furthermore, we have defined significantly elevated levels of MMSET, MYD88, c-Myc, CD243, Notch-1, and CD47 from hematopoietic stem cells to PCs in myeloma B cell lymphopoiesis, noted even in premalignant conditions, with variably modulated expression of B cell development regulators, including IRF-4, Bcl-2, Bcl-6, and sXBP-1; aberrant PC markers (such as CD52, CD44, CD200, CD81, CD269, CD117, and CXCR4); and stemness-controlling regulators, including Nanog, KLF-4, octamer-binding transcription factor 3/4 (Oct3/4), Sox2, and retinoic acid receptor α2 (RARα2). This study provides the rationale for precise molecular profiling of patients with MM by CyTOF technology to define disease heterogeneity and prognosis.
为了更好地描述多发性骨髓瘤（MM）的异质性，我们通过质谱流式细胞术（CyTOF）分析，对意义未明单克隆丙种球蛋白血症、冒烟型 MM 和活动性 MM 患者的 BM 样本中的浆细胞（PCs）及其 B 细胞淋巴发生进行了分析。恶性浆母细胞和 PCs 内和内瘤异质性的特征表明，MM SET 结构域（MMSET）、Notch-1 和 CD47 的过度表达。B 细胞信号转导调节剂（干扰素调节因子 4 [IRF-4]、CXCR4、B 细胞淋巴瘤 6 [Bcl-6]、c-Myc、髓样分化初级反应蛋白 88 [MYD88]和剪接 X 盒结合蛋白 1 [sXBP-1]）和异常标志物（CD319、CD269、CD200、CD117、CD56 和 CD28）的上调变化与克隆 PC 亚群的不同临床结局相关。此外，预后与干性标志物亚克隆表达的异质性有关，包括神经上皮干细胞蛋白（Nestin）、SRY 盒转录因子 2（Sox2）、Krüppel 样因子 4（KLF-4）和 Nanog。此外，我们已经定义了在骨髓瘤 B 细胞淋巴发生中从造血干细胞到 PCs 中 MMSET、MYD88、c-Myc、CD243、Notch-1 和 CD47 的水平显著升高，甚至在癌前状态下也可以观察到，B 细胞发育调节剂的表达也发生了不同程度的调节，包括 IRF-4、Bcl-2、Bcl-6 和 sXBP-1；异常的 PC 标志物（如 CD52、CD44、CD200、CD81、CD269、CD117 和 CXCR4）；以及干性调控因子，包括 Nanog、KLF-4、八聚体结合转录因子 3/4（Oct3/4）、Sox2 和维甲酸受体 α2（RARα2）。本研究为通过 CyTOF 技术对 MM 患者进行精确的分子谱分析提供了依据，以定义疾病异质性和预后。
