文章：

多发性骨髓瘤：进化的遗传事件和宿主相互作用

Multiple myeloma: evolving genetic events and host interactions

原文发布日期：2002-03-01

DOI: 10.1038/nrc746

类型: Review Article

开放获取: 否

要点：

1. Multiple myeloma, which is located at multiple sites in the bone-marrow compartment, is a malignant plasma-cell tumour that is characterized by osteolytic bone lesions. It is a slowly proliferating tumour, typically with less than 1% of tumour cells synthesizing DNA, until late in the disease, when multiple myeloma cells are often found outside the bone marrow.
2. A pre-malignant lesion called monoclonal gammopathy of undetermined significance (MGUS), which is present in 1% of adults, progresses to malignant multiple myeloma at a rate of 1% per year.
3. The karyotypes of multiple myeloma are complex, and more similar to those found in epithelial tumours and the blast phase of chronic myelogenous leukaemia than to those in other haematopoietic tumours.
4. Primary translocations — mediated by errors in B-cell-specific DNA modification processes — juxtapose one or more oncogenes and immunoglobulin transcriptional regulatory regions in ∼50% of MGUS and multiple myelomas. In contrast to other B-cell malignancies, these translocations simultaneously dysregulate a variety of oncogenes, such as the genes for cyclin D1 or D3, fibroblast growth factor receptor 3 (FGFR3) combined with the nuclear protein MMSET, and the transcription factor c-MAF.
5. Secondary translocations that do not involve B-cell-specific processes contribute to progression by dysregulating other oncogenes. Although c-MYC is dysregulated by primary translocations in some B-cell malignancies, it is dysregulated by secondary translocations, often without involvement of an immunogloublin locus, as myeloma tumours become more proliferative at a late stage of progression.
6. Genetic changes are similar in pre-malignant MGUS and multiple myeloma, although the latter is distinguished by the presence of activating mutations of NRAS or KRAS2, and also a higher incidence of monosomy 13, indicating a possible tumour-suppressor gene on chromosome 13.
7. Normal plasma cells, as well as MGUS and multiple myeloma cells, are dependent on the bone-marrow microenvironment for survival, growth and differentiation. These processes are, in part, mediated by paracrine interleukin-6 and insulin-like growth factor 1. The evolving interaction of multiple myeloma cells with the bone-marrow microenvironment is also involved in the secondary effects of malignancy, including osteolysis, anaemia and immunodeficiency.
8. Multiple myeloma is an incurable malignancy for which the median survival has remained fixed at about 3 years for the past decade. Although MGUS can be efficiently diagnosed by a simple blood test, it is not possible to prevent progression or even predict when progression to myeloma will occur. Recent advances in understanding the molecular pathogenesis of these tumours indicate that improved approaches for prevention and treatment should be possible in the near future.

要点翻译：

1. 多发性骨髓瘤是一种恶性浆细胞肿瘤，发生于骨髓腔内的多个部位，以溶骨性病变为特征。这是一种增殖缓慢的肿瘤，在疾病晚期之前通常只有不到1%的肿瘤细胞合成DNA，直至疾病晚期才常在骨髓外发现骨髓瘤细胞。
2. 约1%的成年人存在一种称为意义未明单克隆丙种球蛋白病（MGUS）的癌前病变，其以每年1%的比例向恶性多发性骨髓瘤进展。
3. 多发性骨髓瘤的核型复杂程度更接近于上皮肿瘤和慢性粒细胞白血病急变期，而非其他造血系统肿瘤。
4. 约50%的MGUS和多发性骨髓瘤病例中，B细胞特异性DNA修饰过程错误介导的原发性易位使一个或多个癌基因与免疫球蛋白转录调控区相邻。与其他B细胞恶性肿瘤不同，这些易位同时调控多种癌基因，如细胞周期蛋白D1或D3基因、成纤维细胞生长因子受体3（FGFR3）与核蛋白MMSET的组合，以及转录因子c-MAF。
5. 不涉及B细胞特异性过程的继发性易位通过调控其他癌基因促进疾病进展。虽然c-MYC在某些B细胞恶性肿瘤中受原发性易位调控，但在骨髓瘤进展晚期增殖活性增强时，它往往通过不涉及免疫球蛋白基因座的继发性易位实现调控。
6. 癌前病变MGUS与多发性骨髓瘤的遗传学改变相似，但后者以存在NRAS或KRAS2激活突变及更高比例的第13号染色体单体为特征，提示13号染色体上可能存在抑癌基因。
7. 正常浆细胞以及MGUS和多发性骨髓瘤细胞的生存、生长和分化都依赖于骨髓微环境。这些过程部分由旁分泌白细胞介素-6和胰岛素样生长因子1介导。骨髓瘤细胞与骨髓微环境之间不断演变的相互作用也参与了恶性病变的继发效应，包括骨溶解、贫血和免疫缺陷。
8. 多发性骨髓瘤是一种无法治愈的恶性肿瘤，过去十年中其中位生存期始终维持在3年左右。虽然MGUS可通过简单血液检测有效诊断，但目前既无法阻止其进展，甚至无法预测何时会进展为骨髓瘤。近年来对这些肿瘤分子发病机制的认识取得进展，表明在不久的将来可能找到改进的预防和治疗方法。

英文摘要：

Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers. Unlike most haematopoietic cancers, multiple myeloma often has complex chromosomal abnormalities that are reminiscent of epithelial tumours. What causes full-blown myeloma? And can our molecular understanding of this common haematological malignancy be used to develop effective preventive and treatment strategies?

摘要翻译： 

多发性骨髓瘤是终末分化的B细胞（浆细胞）的肿瘤，其染色体易位经常将癌基因置于免疫球蛋白增强子的控制之下。与大多数血液系统癌症不同，多发性骨髓瘤常具有复杂的染色体异常，类似于上皮性肿瘤。什么原因导致完全型骨髓瘤的发生？我们对这种常见血液系统恶性肿瘤的分子理解能否用于开发有效的预防和治疗策略？

原文链接：

Multiple myeloma: evolving genetic events and host interactions