Fennell, Katie A. and Vassiliadis, Dane and Lam, Enid Y. N. and Martelotto, Luciano G. and Balic, Jesse J. and Hollizeck, Sebastian and Weber, Tom S. and Semple, Timothy and Wang, Qing and Miles, Denise C. and MacPherson, Laura and Chan, Yih-Chih and Guirguis, Andrew A. and Kats, Lev M. and Wong, Emily S. and Dawson, Sarah-Jane and Naik, Shalin H. and Dawson, Mark A. (2022) Non-genetic determinants of malignant clonal fitness at single-cell resolution. Nature, 601 (7891). pp.125-131. ISSN 0028-0836
Full text not available from this repository.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 clear(1), little is known about the non-genetic mechanisms that contribute to intratumour heterogeneity and malignant clonal fitness(2). 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(3), 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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 14 Apr 2022 04:23 |
| Last Modified: | 14 Apr 2022 04:23 |
| URI: | http://eprints.victorchang.edu.au/id/eprint/1220 |
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