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研究揭示单细胞分辨率下恶性克隆适应性的非遗传决定因素
2021-12-11 21:44
来源：小柯机器人

澳大利亚墨尔本大学Mark A. Dawson团队揭示单细胞分辨率下恶性克隆适应性的非遗传决定因素。2021年12月8日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员利用单细胞分析和系谱追踪（SPLINTR），在三种临床相关的急性骨髓性白血病小鼠模型中追踪了同源克隆。研究人员发现，恶性克隆优势是一种细胞内在的和可遗传的特性，它通过抑制抗原呈递和增加分泌型白细胞肽酶抑制剂基因（Slpi）的表达而得到促进，研究人员从基因上验证了它是急性骨髓性白血病的一个调节因子。转录异质性的增加是在不同组织和免疫微环境中以及在基因不同的克隆之间的克隆竞争的背景下使克隆适应的一个特征。与造血干细胞相似，白血病干细胞（LSC）显示出可遗传的克隆内在特性，即高和低的克隆输出，有助于整个肿瘤的质量。
 
研究人员证明，LSC的克隆输出决定了对化疗的敏感性，虽然高输出和低输出的克隆对治疗压力的适应性不同，但它们会随着LSC程序表达的增加而协调地从最小残留灶中出现。总之，这些数据提供了对非遗传转录过程的基本见解，这些转录过程支撑着恶性克隆的健康，并可能改变未来的治疗策略。
 
据了解，所有的癌症都是在经过一段时间的克隆选择和随后的克隆扩张后出现的。尽管遗传性的瘤内异质性所带来的进化原理越来越清晰，但对于促成瘤内异质性和恶性克隆的非遗传机制却知之甚少。
 
附：英文原文

Title: Non-genetic determinants of malignant clonal fitness at single-cell resolution

Author: Fennell, Katie A., Vassiliadis, Dane, Lam, Enid Y. N., Martelotto, Luciano G., Balic, Jesse J., Hollizeck, Sebastian, Weber, Tom S., Semple, Timothy, Wang, Qing, Miles, Denise C., MacPherson, Laura, Chan, Yih-Chih, Guirguis, Andrew A., Kats, Lev M., Wong, Emily S., Dawson, Sarah-Jane, Naik, Shalin H., Dawson, Mark A.

Issue&Volume: 2021-12-08

Abstract: All cancers emerge after a period of clonal selection and subsequent clonal expansion. Although the evolutionary principles imparted by genetic intratumour heterogeneity are becoming increasingly clear1, little is known about the non-genetic mechanisms that contribute to intratumour heterogeneity and malignant clonal fitness2. Here, using single-cell profiling and lineage tracing (SPLINTR)—an expressed barcoding strategy—we trace isogenic clones in three clinically relevant mouse models of acute myeloid leukaemia. We find that malignant clonal dominance is a cell-intrinsic and heritable property that is facilitated by the repression of antigen presentation and increased expression of the secretory leukocyte peptidase inhibitor gene (Slpi), which we genetically validate as a regulator of acute myeloid leukaemia. Increased transcriptional heterogeneity is a feature that enables clonal fitness in diverse tissues and immune microenvironments and in the context of clonal competition between genetically distinct clones. Similar to haematopoietic stem cells3, leukaemia stem cells (LSCs) display heritable clone-intrinsic properties of high, and low clonal output that contribute to the overall tumour mass. We demonstrate that LSC clonal output dictates sensitivity to chemotherapy and, although high- and low-output clones adapt differently to therapeutic pressure, they coordinately emerge from minimal residual disease with increased expression of the LSC program. Together, these data provide fundamental insights into the non-genetic transcriptional processes that underpin malignant clonal fitness and may inform future therapeutic strategies.

DOI: 10.1038/s41586-021-04206-7

Source: https://www.nature.com/articles/s41586-021-04206-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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