Sahota Surinder S, Forconi Francesco, Ottensmeier Christian H, Stevenson Freda K
Molecular Immunology Group, Tenovus Laboratory, Cancer Sciences Division, Southampton University Hospitals, UK.
Semin Oncol. 2003 Apr;30(2):136-41. doi: 10.1053/sonc.2003.50072.
Histopathology and phenotypic considerations in IgM-secreting B-cell tumors allow distinction between different diseases, but insight into pathogenesis is restricted. Here, variable region (V) gene analysis can complement classification but, more importantly, can also reveal disease origins and clonal history. We used V(H) gene analysis to probe origins in Waldenstrom's macroglobulinemia (WM), and contrasted these with the less malignant counterpart, IgM-secreting monoclonal gammopathy of undetermined significance (MGUS). Limited data on WM sequences had previously shown evidence for somatic mutation, but with conflicting analysis of intraclonal variation in tumor sequences. To further the investigation, we analyzed seven cases of WM and compared these with three cases of IgM MGUS. In both diseases, V(H) genes were somatically mutated with no evidence of intraclonal variation, even at the MGUS stage. A sensitive V(H) gene-probe assay revealed no evidence for isotype switch transcripts in any of the WM and IgM MGUS cases. These findings reveal an origin of WM and IgM MGUS from a IgM cell, which transforms after cessation of somatic mutation but without initiating switch events. In contrast, IgM-secreting multiple myeloma arises at a later stage in differentiation, when isotype switch mechanisms have been engaged.
分泌 IgM 的 B 细胞肿瘤的组织病理学和表型特征有助于区分不同疾病，但对发病机制的了解有限。在此，可变区（V）基因分析可补充分类，但更重要的是，还可揭示疾病起源和克隆历史。我们使用 V（H）基因分析来探究华氏巨球蛋白血症（WM）的起源，并将其与恶性程度较低的对应疾病——意义未明的 IgM 分泌型单克隆丙种球蛋白病（MGUS）进行对比。此前关于 WM 序列的有限数据已显示出体细胞突变的证据，但对肿瘤序列中克隆内变异的分析存在矛盾。为进一步开展研究，我们分析了 7 例 WM 病例，并将其与 3 例 IgM MGUS 病例进行比较。在这两种疾病中，V（H）基因均发生了体细胞突变，且在任何病例中均未发现克隆内变异的证据，即使在 MGUS 阶段也是如此。一种灵敏的 V（H）基因探针检测法显示，在任何 WM 和 IgM MGUS 病例中均未发现同种型转换转录本的证据。这些发现揭示了 WM 和 IgM MGUS 起源于 IgM 细胞，该细胞在体细胞突变停止后发生转化，但未启动转换事件。相比之下，分泌 IgM 的多发性骨髓瘤在分化后期出现，此时同种型转换机制已启动。
