Sahota S, Hamblin T, Oscier D G, Stevenson F K
Molecular Immunology Group, Tenovus Laboratory, Southampton University Hospitals, UK.
Leukemia. 1994 Aug;8(8):1285-9.
The identifiable neoplastic cell in multiple myeloma is the plasma cell, which usually synthesizes and secretes a monoclonal immunoglobulin. However, there exists the possibility that the neoplastic event has occurred in a less mature clonally-related cell, such as a B lymphocyte, prior to Ig class switching. Since the presence of such a clonogenic cell could influence design of therapy, particularly with monoclonal antibodies, we have used the analysis of tumour-related VH genes to approach this question. Cloning and sequencing of PCR products from VH genes of tumour cells obtained from 4/4 patients with myeloma revealed significant mutation of the genes as compared to germ line sequences. In all cases the mutations were scattered throughout the variable region, with a pattern which did not indicate a role for antigen in selection. Importantly for therapy, multiple VH sequences from all patients were completely homogeneous, with no intraclonal variation. These findings indicate that, although IgM-positive clonogenic cells may exist, it is unlikely that they are involved in continuous maintenance of the malignant isotype-switched cell population. One possibility is that the B-cell progenitor population has to undergo further chromosomal changes to generate the malignant cell, and that this occurs at a more mature stage; in this case, antibody therapy should be aimed primarily at the more differentiated cells.
多发性骨髓瘤中可识别的肿瘤细胞是浆细胞，它通常合成并分泌单克隆免疫球蛋白。然而，在免疫球蛋白类别转换之前，肿瘤事件有可能发生在一个不太成熟的克隆相关细胞中，比如B淋巴细胞。由于这种克隆源性细胞的存在可能会影响治疗方案的设计，尤其是单克隆抗体治疗，我们通过分析肿瘤相关的VH基因来探讨这个问题。对4例骨髓瘤患者肿瘤细胞的VH基因PCR产物进行克隆和测序，结果显示与种系序列相比，这些基因有显著突变。在所有病例中，突变分散在整个可变区，其模式并不表明抗原在选择中起作用。对治疗而言重要的是，所有患者的多个VH序列完全一致，没有克隆内变异。这些发现表明，虽然可能存在IgM阳性的克隆源性细胞，但它们不太可能参与恶性类别转换细胞群体的持续维持。一种可能性是B细胞祖细胞群体必须经历进一步的染色体变化才能产生恶性细胞，而这种变化发生在更成熟的阶段；在这种情况下，抗体治疗应主要针对分化程度更高的细胞。
