文章：

多发性骨髓瘤的遗传结构

The genetic architecture of multiple myeloma

原文发布日期：2012-04-12

DOI: 10.1038/nrc3257

类型: Review Article

开放获取: 否

要点：

1. The initiation of myeloma is mediated by the interaction of environmental factors and inherited genetic events that, when combined with the normal physiological processes that are necessary to generate antibody diversity, result in genetic changes that lead to the immortalization of a myeloma-propagating cell. Chief among these events are chromosomal translocations and hyperdiploidy.
2. Based on their distribution in most clonal cells, chromosomal translocations that are generated by aberrant class switch recombination have been suggested to be initiating events occurring early in the disease process. As a result of these translocations, oncogenes can be placed under the control of the strong enhancers of the immunoglobulin gene loci, leading to their increased expression.
3. The interaction of normal plasma cells with their supportive microenvironment is crucial for plasma cell longevity. A characteristic feature of myeloma cells is the requirement for an intimate relationship with the bone marrow microenvironment, where plasma cells are nurtured in specialized niches that facilitate the growth of the myeloma clone. Derangement of these interactions is important in the immortalization of a myeloma-propagating cell.
4. The basic premise underlying the progression of myeloma is that multiple mutations in different pathways collaborate to deregulate the intrinsic biology of the plasma cell, changing it in ways that lead to the features of myeloma. The immortalized cell then acquires additional genetic hits over time, thus leading to the clinically recognized features of myeloma and eventually to the development of treatment resistance and an ability to grow in the peripheral blood as a leukaemic phase.
5. It is becoming increasingly clear that the molecular events acquired during myeloma progression are not acquired in a linear fashion but instead through branching, nonlinear pathways, similar to the mechanism suggested by Darwin to explain the evolution of species. Therefore, a further level of the genetic complexity of myeloma is based on intraclonal heterogeneity at the level of a myeloma-propagating cell.
6. The genetic lesions that lead to myeloma are best considered within the categories of inherited variation, translocations, copy number abnormalities, mutations, and methylation and miRNA abnormalities. The net biological impact of such events is to modify the behaviour of the myeloma-propagating cell, resulting in the key molecular hallmarks of myeloma.
7. The treatments that are used for myeloma include steroids, alkylating agents, the immunomodulatory drugs thalidomide and lenalidomide, proteasome inhibitors and autologous stem cell transplantation. Current therapeutic aims are to induce and maintain long-term remission. Future approaches based on personalized medicine strategies will involve targeted therapies combined with molecular-diagnostic strategies.
8. The presence of intraclonal heterogeneity has important effects on the clinical application of both standard and targeted treatment strategies but provides a model system within which to assess their optimum use.

要点翻译：

1. 骨髓瘤的发生由环境因素与遗传事件相互作用介导，这些因素与产生抗体多样性所必需的正常生理过程相结合，导致遗传学改变，最终引起骨髓瘤干细胞的永生化。其中最主要的遗传事件包括染色体易位和高二倍体。
2. 基于在大多数克隆细胞中的分布情况，由异常类别转换重组引发的染色体易位被认为是疾病进程早期的起始事件。这些易位使癌基因受免球蛋白基因位点的强增强子调控，导致其表达水平升高。
3. 正常浆细胞与其支持性微环境的相互作用对浆细胞存活至关重要。骨髓瘤细胞的一个典型特征是需要与骨髓微环境建立密切关联，在特化的生态位中浆细胞获得滋养，从而促进骨髓瘤克隆的生长。这些相互作用的紊乱对骨髓瘤干细胞的永生化至关重要。
4. 骨髓瘤进展的基本前提是：不同通路中的多重突变共同作用，导致浆细胞内在生物学特性失调，进而转化为具有骨髓瘤特征的细胞。永生化细胞随时间推移获得更多遗传学打击，从而出现临床可识别的骨髓瘤特征，最终发展为治疗耐药并具备在外周血中呈白血病样生长的能力。
5. 日益明确的是，骨髓瘤进展过程中获得的分子事件并非以线性方式发生，而是通过分支状、非线性的途径获得，这与达尔文解释物种进化的机制相似。因此，骨髓瘤遗传复杂性的另一个层面在于骨髓瘤干细胞水平的克隆内异质性。
6. 导致骨髓瘤的遗传学损伤最好从遗传变异、易位、拷贝数异常、基因突变、甲基化及miRNA异常等类别进行考量。这些事件的净生物学效应是改变骨髓瘤干细胞的行为，从而形成骨髓瘤的关键分子特征。
7. 骨髓瘤的治疗手段包括类固醇、烷化剂、免疫调节药物（沙利度胺和来那度胺）、蛋白酶体抑制剂及自体干细胞移植。当前的治疗目标是诱导并维持长期缓解。基于个体化医疗策略的未来方案将结合分子诊断技术实施靶向治疗。
8. 克隆内异质性的存在对标准治疗和靶向治疗策略的临床应用具有重要影响，但为此提供了一个评估最佳治疗方案的模型系统。

英文摘要：

Based on the clinical features of myeloma and related malignancies of plasma cells, it has been possible to generate a model system of myeloma progression from a normal plasma cell through smouldering myeloma to myeloma and then plasma cell leukaemia. Using this model system we can study at which points the genetic alterations identified through whole-tumour molecular analyses function in the initiation and progression of myeloma. Further genetic complexity, such as intraclonal heterogeneity, and insights into the molecular evolution and intraclonal dynamics in this model system are crucial to our understandings of tumour progression, treatment resistance and the use of currently available and future treatments.

摘要翻译： 

基于骨髓瘤及浆细胞相关恶性肿瘤的临床特征，已可构建从正常浆细胞经冒烟型骨髓瘤发展为骨髓瘤，最终进展为浆细胞白血病的模型体系。利用该模型，我们能够研究通过全肿瘤分子分析发现的遗传变异在骨髓瘤发生与进展中的具体作用节点。进一步的遗传复杂性，如克隆内异质性，以及对该模型中分子演化和克隆内动态的深入理解，对于认识肿瘤进展、治疗耐药及指导现有和未来治疗策略至关重要。

原文链接：

The genetic architecture of multiple myeloma