Longitudinal single-cell analysis of a myeloma mouse model identifies subclonal molecular programs associated with progression.
Longitudinal single-cell analysis of a myeloma mouse model identifies subclonal molecular programs associated with progression.
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DOI：
10.1038/s41467-021-26598-w
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发表时间：
2021-11-03
影响因子：
16.6
通讯作者：
Trudel S
中科院分区：
文献类型：
--
作者：
Croucher DC;Richards LM;Tsofack SP;Waller D;Li Z;Wei EN;Huang XF;Chesi M;Bergsagel PL;Sebag M;Pugh TJ;Trudel S
导致多发性骨髓瘤前体进展的分子程序尚不完全清楚。在这里，我们报告了Vκ*MYC骨髓瘤小鼠模型的疾病谱跨越，单细胞分析。使用从血清学上无法检测到疾病的小鼠身上获得的样本，我们早在30周龄时就发现了恶性细胞，并表明这些肿瘤含有亚克隆拷贝数变异，这种变异在整个进展过程中持续存在。我们检测了活动性疾病期间由转录变异性驱动的肿瘤内异质性，并表明亚克隆表达程序在早期疾病的不同时间富集。然后，我们展示了一个与GCN2应激反应相关的亚克隆程序是如何在骨髓瘤患者的进展过程中逐渐激活的。最后，我们在体外使用GCN2的化学和遗传扰动来支持该途径作为骨髓瘤的治疗靶点。因此，这些发现提出了Vκ*MYC小鼠前体进展的模型，提出了对骨髓瘤存活重要的适应性机制，并强调了单细胞分析以了解疾病进展的生物学基础的必要性。导致多发性骨髓瘤（MM）进展的分子程序尚不完全清楚。在这里，作者使用小鼠MM模型和单细胞RNA-seq来定义在进展过程中出现的亚克隆表达程序，并为靶向治疗策略提供信息。
Molecular programs that underlie precursor progression in multiple myeloma are incompletely understood. Here, we report a disease spectrum-spanning, single-cell analysis of the Vκ*MYC myeloma mouse model. Using samples obtained from mice with serologically undetectable disease, we identify malignant cells as early as 30 weeks of age and show that these tumours contain subclonal copy number variations that persist throughout progression. We detect intratumoural heterogeneity driven by transcriptional variability during active disease and show that subclonal expression programs are enriched at different times throughout early disease. We then show how one subclonal program related to GCN2 stress response is progressively activated during progression in myeloma patients. Finally, we use chemical and genetic perturbation of GCN2 in vitro to support this pathway as a therapeutic target in myeloma. These findings therefore present a model of precursor progression in Vκ*MYC mice, nominate an adaptive mechanism important for myeloma survival, and highlight the need for single-cell analyses to understand the biological underpinnings of disease progression. The molecular programs that underlie progression in multiple myeloma (MM) are incompletely understood. Here the authors use a mouse model of MM and single-cell RNA-seq to define subclonal expression programs that arise during progression and that inform targeted therapeutic strategies.
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影响因子：
5.8
作者：
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通讯作者：
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影响因子：
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