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
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
Nature. 2022 Jan;601(7891):125-131. doi: 10.1038/s41586-021-04206-7. Epub 2021 Dec 8.
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 clear, little is known about the non-genetic mechanisms that contribute to intratumour heterogeneity and malignant clonal fitness. 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 cells, 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.
所有癌症都经过一段克隆选择期及随后的克隆扩增后出现。尽管肿瘤内基因异质性所赋予的进化原理日益清晰，但对于促成肿瘤内异质性和恶性克隆适应性的非遗传机制却知之甚少。在此，我们利用单细胞分析和谱系追踪（SPLINTR）——一种表达条形码策略——在三种临床相关的急性髓系白血病小鼠模型中追踪同基因克隆。我们发现恶性克隆优势是一种细胞内在的可遗传特性，其受到抗原呈递抑制和分泌型白细胞肽酶抑制剂基因（Slpi）表达增加的促进，我们通过基因验证该基因是急性髓系白血病的一个调节因子。转录异质性增加是一种特性，它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背景下使克隆具有适应性。与造血干细胞类似，白血病干细胞（LSC）表现出高克隆输出和低克隆输出的可遗传克隆内在特性，这对肿瘤总体积有贡献。我们证明LSC克隆输出决定了对化疗的敏感性，并且尽管高输出和低输出克隆对治疗压力的适应方式不同，但它们从微小残留病中协同出现时LSC程序的表达增加。总之，这些数据为支撑恶性克隆适应性的非遗传转录过程提供了基本见解，并可能为未来的治疗策略提供参考。
