文章：

了解多发性骨髓瘤在骨髓中的发病机制，寻找新的治疗靶点

Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets

原文发布日期：2007-08-01

DOI: 10.1038/nrc2189

类型: Review Article

开放获取: 否

要点：

1. Multiple myeloma is a currently incurable B-cell malignancy characterized by excess monotypic plasma cells in the bone marrow in association with an excess of monoclonal protein in serum and/or urine.
2. Multiple myeloma has complex heterogeneous cytogenetic abnormalities. Approximately 55–60% of patients have a hyperdiploid karyotype, which confers a better prognosis than those with non-hyperdiploid disease. Most non-hyperdiploid tumours have IgH translocations that involve several recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), 16q23 (MAF) and 20q11 (MAFB). Recent genomic and expression-profiling studies have both identified new therapeutic targets and provided the framework for a genetically based prognostic classification of multiple myeloma.
3. These constitutive genetic alterations in multiple myeloma cells and changes in gene-expression profiles mediate the protective effects of the bone marrow microenvironment on multiple myeloma cells.
4. Multiple myeloma cells that home to the bone marrow have important functional sequelae. Specifically, the adhesion of multiple myeloma cells to extracellular matrix proteins confers cell adhesion-mediated drug resistance (CAMDR), and the binding of multiple myeloma cells to bone marrow accessory cells triggers the secretion of cytokines, which not only promote growth, survival and migration of multiple myeloma cells, but also confer resistance to conventional chemotherapy. Targeting these mechanisms offers a potential therapeutic strategy to overcome drug resistance.
5. Several factors, including MIP1α and RANKL, stimulate osteoclast activity; on the other hand, DKK1 inhibits osteoblastogenesis in multiple myeloma. This imbalance between bone formation and resorption results in osteolytic lesions, which are a hallmark of multiple myeloma.
6. New agents that target multiple myeloma cells, tumour–bone marrow interactions, or the bone marrow milieu, used alone or in combination, have shown promise in overcoming conventional drug resistance and improving patient outcome in multiple myeloma. Oncogenomics will allow for both patient selection and rational combination therapeutics.

要点翻译：

1. 多发性骨髓瘤是一种目前无法治愈的B细胞恶性肿瘤，其特征是骨髓中存在过量的单克隆浆细胞，同时血清和/或尿液中存在过量单克隆蛋白。
2. 多发性骨髓瘤具有复杂的异质性细胞遗传学异常。约55%-60%的患者具有超二倍体核型，这类患者的预后优于非超二倍体患者。大多数非超二倍体肿瘤存在涉及多个复发性染色体位点的IgH易位，包括11q13（细胞周期蛋白D1）、6p21（细胞周期蛋白D3）、4p16（FGFR3和MMSET）、16q23（MAF）及20q11（MAFB）。近期基因组学与表达谱研究不仅确定了新的治疗靶点，更为建立基于遗传学的多发性骨髓瘤预后分类体系提供了框架。
3. 多发性骨髓瘤细胞的这些固有遗传改变及基因表达谱的变化介导了骨髓微环境对肿瘤细胞的保护效应。
4. 归巢至骨髓的多发性骨髓瘤细胞会产生重要功能性后遗症。具体而言，瘤细胞与细胞外基质蛋白的粘附会引发细胞粘附介导的耐药性（CAMDR），而瘤细胞与骨髓辅助细胞的结合会触发细胞因子分泌，这些因子不仅促进肿瘤细胞的生长、存活和迁移，还导致对传统化疗的耐药性。针对这些机制的治疗策略为克服耐药性提供了潜在可能。
5. 包括MIP1α和RANKL在内的多种因子会刺激破骨细胞活性；另一方面，DKK1会抑制多发性骨髓瘤中的成骨细胞生成。这种骨形成与骨吸收之间的失衡导致溶骨性病变，这是多发性骨髓瘤的典型特征。
6. 针对多发性骨髓瘤细胞、肿瘤-骨髓相互作用或骨髓微环境的新药，无论是单独使用还是联合应用，在克服传统耐药性和改善患者预后方面均展现出良好前景。肿瘤基因组学将为实现患者筛选和合理化联合治疗提供支持。

英文摘要：

Multiple myeloma is a plasma cell malignancy characterized by complex heterogeneous cytogenetic abnormalities. The bone marrow microenvironment promotes multiple myeloma cell growth and resistance to conventional therapies. Although multiple myeloma remains incurable, novel targeted agents, used alone or in combination, have shown great promise to overcome conventional drug resistance and improve patient outcome. Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.

摘要翻译： 

多发性骨髓瘤是一种浆细胞恶性肿瘤，其特征为复杂且异质性明显的细胞遗传学异常。骨髓微环境促进骨髓瘤细胞的生长，并使其对传统治疗产生耐药性。尽管多发性骨髓瘤目前仍无法治愈，但新型靶向药物单用或联合应用，在克服传统耐药和改善患者预后方面展现出巨大潜力。近年来肿瘤基因组学研究进一步深化了我们对多发性骨髓瘤分子发病机制的认识，为新的预后分类提供了框架，并识别出新的治疗靶点。

原文链接：

Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets