Cowan Graeme, Weston-Bell Nicola J, Bryant Dean, Seckinger Anja, Hose Dirk, Zojer Niklas, Sahota Surinder S
Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, University of Edinburgh, UK.
Tumour Immunogenetics Group, Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, UK.
Oncotarget. 2015 May 30;6(15):13229-40. doi: 10.18632/oncotarget.3644.
Human multiple myeloma (MM) is characterized by accumulation of malignant terminally differentiated plasma cells (PCs) in the bone marrow (BM), raising the question when during maturation neoplastic transformation begins. Immunoglobulin IGHV genes carry imprints of clonal tumor history, delineating somatic hypermutation (SHM) events that generally occur in the germinal center (GC). Here, we examine MM-derived IGHV genes using massive parallel deep sequencing, comparing them with profiles in normal BM PCs. In 4/4 presentation IgG MM, monoclonal tumor-derived IGHV sequences revealed significant evidence for intraclonal variation (ICV) in mutation patterns. IGHV sequences of 2/2 normal PC IgG populations revealed dominant oligoclonal expansions, each expansion also displaying mutational ICV. Clonal expansions in MM and in normal BM PCs reveal common IGHV features. In such MM, the data fit a model of tumor origins in which neoplastic transformation is initiated in a GC B-cell committed to terminal differentiation but still targeted by on-going SHM. Strikingly, the data parallel IGHV clonal sequences in some monoclonal gammopathy of undetermined significance (MGUS) known to display on-going SHM imprints. Since MGUS generally precedes MM, these data suggest origins of MGUS and MM with IGHV gene mutational ICV from the same GC B-cell, arising via a distinctive pathway.
人类多发性骨髓瘤（MM）的特征是恶性终末分化浆细胞（PC）在骨髓（BM）中积聚，这就引发了肿瘤转化在成熟过程中的何时开始的问题。免疫球蛋白IGHV基因带有克隆肿瘤历史的印记，描绘了通常发生在生发中心（GC）的体细胞超突变（SHM）事件。在这里，我们使用大规模平行深度测序检查MM来源的IGHV基因，并将它们与正常BM PC中的图谱进行比较。在4/4例呈现IgG的MM中，单克隆肿瘤来源的IGHV序列显示出突变模式中存在克隆内变异（ICV）的显著证据。2/两个正常PC IgG群体的IGHV序列显示出显性寡克隆扩增，每个扩增也显示出突变ICV。MM和正常BM PC中的克隆扩增显示出共同的IGHV特征。在这种MM中，数据符合肿瘤起源模型，其中肿瘤转化在致力于终末分化但仍受正在进行的SHM靶向的GC B细胞中启动。引人注目的是，这些数据与一些已知显示正在进行的SHM印记的意义未明的单克隆丙种球蛋白病（MGUS）中的IGHV克隆序列相似。由于MGUS通常先于MM出现，这些数据表明MGUS和MM的起源是来自同一个GC B细胞的具有IGHV基因突变ICV的，通过一条独特的途径产生。
