Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma
Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma
复制标题
DOI：
10.1038/leu.2014.13
复制
发表时间：
2014-08-01
期刊：
影响因子：
11.4
通讯作者：
Morgan, G. J.
中科院分区：
文献类型：
--
作者：
Melchor, L.;Brioli, A.;Morgan, G. J.
尽管已推断多发性骨髓瘤（MM）存在瘤内异质性，但对其亚克隆系统发育知之甚少。为了描述一系列MM患者的系统发育树，我们进行了全外显子组测序和单细胞遗传分析。我们的研究结果表明，在介绍nnyeloma是由2至6个不同的主要克隆，这是相关的线性和分支的同源性。值得注意的是，最早的骨髓瘤起始克隆，其中一些只有起始t（11;14），在诊断时仍然以低频率存在。对于第一次在骨髓瘤中，我们证明了平行进化，即两个独立的克隆激活RAS/MAPK途径通过RAS突变，并随后产生不同的亚克隆谱系。我们还报告了4%的骨髓瘤患者同时发生RAS和干扰素调节因子4（IRF 4）p.K123R突变。最后，我们描述了一名患者在发病和复发时以及在NOD/SCID-IL 2 R γ（无效）异种移植物中骨髓瘤亚克隆结构的波动，揭示了克隆灭绝和获得额外突变的新克隆的出现。本研究证实，骨髓瘤亚克隆在治疗或小鼠移植期间表现出不同的存活特性。我们的结论是，克隆多样性结合不同的选择压力是骨髓瘤肿瘤进展和治疗耐药的重要基础。
Although intratumor heterogeneity has been inferred in multiple myeloma (MM), little is known about its subclonal phylogeny. To describe such phylogenetic trees in a series of patients with MM, we perform whole-exome sequencing and single-cell genetic analysis. Our results demonstrate that at presentation nnyeloma is composed of two to six different major clones, which are related by linear and branching phylogenies. Remarkably, the earliest myeloma-initiating clones, some of which only had the initiating t(11;14), were still present at low frequencies at the time of diagnosis. For the first time in myeloma, we demonstrate parallel evolution whereby two independent clones activate the RAS/MAPK pathway through RAS mutations and give rise subsequently to distinct subclonal lineages. We also report the co-occurrence of RAS and interferon regulatory factor 4 (IRF4) p.K123R mutations in 4% of myeloma patients. Lastly, we describe the fluctuations of myeloma subclonal architecture in a patient analyzed at presentation and relapse and in NOD/SCID-IL2R gamma(null) xenografts, revealing clonal extinction and the emergence of new clones that acquire additional mutations. This study confirms that myeloma subclones exhibit different survival properties during treatment or mouse engraftment. We conclude that clonal diversity combined with varying selective pressures is the essential foundation for tumor progression and treatment resistance in myeloma.