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Molecular basis of clonal evolution in multiple myeloma.
International Journal of Hematology ( IF 2.1 ) Pub Date : 2020-02-06 , DOI: 10.1007/s12185-020-02829-6
Yusuke Furukawa 1 , Jiro Kikuchi 1
Affiliation  

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, ~ 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.

中文翻译:

多发性骨髓瘤的克隆进化的分子基础。

根据非同义突变的平均数,多发性骨髓瘤(MM)的治疗结果比预期的要差,这与癌症患者的预后大致相关。MM的难治性可能归因于该疾病的复杂基因组结构和克隆行为。在MM中,疾病的发展是通过从具有繁殖潜能的储藏克隆的亚克隆进化的分支模式和/或小克隆的出现来完成的,这些小克隆已经存在于MGUS阶段,并通过选择性压力主要通过治疗剂来胜过其他克隆。每个亚克隆都具有新颖的突变和独特的表型,包括药物敏感性。一般来说,成熟的克隆对蛋白酶体抑制剂(PIs)高度敏感,未成熟的克隆对PI具有抗性,但可以通过免疫调节药物(IMiD)消除。分支进化是不同克隆适应微环境并逃避免疫监视的结果。因此,在这种发展模式下,IMiD对于MM是有效的。相比之下,约有20%的MM在强致癌性驱动因素(例如高风险IgH易位)的背景下中性进化,并且对IMiD具有相对抗性。对基因组情况和克隆进化模式的进一步了解可能有助于开发更有效的MM治疗策略。相比之下,约有20%的MM在强致癌性驱动因素(例如高风险IgH易位)的背景下中性进化,并且对IMiD具有相对抗性。对基因组情况和克隆进化模式的进一步了解可能有助于开发更有效的MM治疗策略。相比之下,约有20%的MM在强致癌性驱动因素(例如高风险IgH易位)的背景下中性进化,并且对IMiD具有相对抗性。对基因组格局和克隆进化模式的进一步了解可能有助于开发更有效的MM治疗策略。
更新日期:2020-02-06
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