Molecular basis of clonal evolution in multiple myeloma
Molecular basis of clonal evolution in multiple myeloma
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DOI：
10.1007/s12185-020-02829-6
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发表时间：
2020-02-06
影响因子：
2.1
通讯作者：
Kikuchi, Jiro
中科院分区：
文献类型：
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作者：
Furukawa, Yusuke;Kikuchi, Jiro
多发性骨髓瘤（MM）的治疗结果比非同义突变的平均数量预期的要差，这与癌症患者的预后大致相关。MM的难治性可能归因于疾病的复杂基因组结构和克隆行为。在MM中，疾病进展是通过从具有繁殖潜力的储库克隆的亚克隆进化的分支模式和/或次要克隆的出现来实现的，次要克隆已经存在于MGUS阶段并且通过主要由治疗剂的选择压力而胜过其他克隆。每个亚克隆都含有新的突变和不同的表型，包括药物敏感性。一般来说，成熟克隆对蛋白酶体抑制剂（PI）高度敏感，而未成熟克隆对PI有抗性，但可以通过免疫调节药物（IMiD）根除。分支进化是不同克隆对微环境的适应性及其逃避免疫监视的结果;因此，IMiD对具有这种进化模式的MM有效。相比之下，在强致癌驱动因素（如高风险IgH易位）的背景下，约20%的MM呈中性进化，并且对IMiD具有相对耐药性。进一步了解基因组景观和克隆进化模式可能有助于开发更有效的MM治疗策略。
The treatment outcome of multiple myeloma (MM) is worse than expected from the average numbers of non-synonymous mutations, which are roughly correlated with the prognosis of cancer patients. The refractoriness of MM may be ascribed to the complex genomic architecture and clonal behavior of the disease. In MM, disease progression is accomplished by branching patterns of subclonal evolution from reservoir clones with a propagating potential and/or the emergence of minor clones, which already exist at the MGUS stage and outcompete other clones through selective pressure mainly by therapeutic agents. Each subclone harbors novel mutations and distinct phenotypes including drug sensitivities. In general, mature clones are highly sensitive to proteasome inhibitors (PIs), whereas immature clones are resistant to PIs but could be eradicated by immunomodulatory drugs (IMiDs). The branching evolution is a result of the fitness of different clones to microenvironment and their evasion of immune surveillance; therefore, IMiDs are effective for MM with this pattern of evolution. In contrast, similar to 20% of MM evolve neutrally in the context of strong oncogenic drivers, such as high-risk IgH translocations, and are relatively resistant to IMiDs. Further understanding of the genomic landscape and the pattern of clonal evolution may contribute to the development of more effective treatment strategies for MM.