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

Katie A. Fennell, Dane Vassiliadis, Enid Y. N. Lam, Luciano G. Martelotto, Jesse J. Balic, Sebastian Hollizeck, Tom S. Weber, Timothy Semple, Qing Wang, Denise C. Miles, Laura MacPherson, Yih-Chih Chan, Andrew A. Guirguis, Lev M. Kats, Emily S. Wong, Sarah-Jane Dawson, Shalin H. Naik and Mark A. Dawson ()
Additional contact information
Katie A. Fennell: Peter MacCallum Cancer Centre
Dane Vassiliadis: Peter MacCallum Cancer Centre
Enid Y. N. Lam: Peter MacCallum Cancer Centre
Luciano G. Martelotto: The University of Melbourne
Jesse J. Balic: Peter MacCallum Cancer Centre
Sebastian Hollizeck: Peter MacCallum Cancer Centre
Tom S. Weber: The Walter and Eliza Hall Institute of Medical Research
Timothy Semple: Peter MacCallum Cancer Centre
Qing Wang: Victor Chang Cardiac Research Institute
Denise C. Miles: The Walter and Eliza Hall Institute of Medical Research
Laura MacPherson: Peter MacCallum Cancer Centre
Yih-Chih Chan: Peter MacCallum Cancer Centre
Andrew A. Guirguis: Peter MacCallum Cancer Centre
Lev M. Kats: Peter MacCallum Cancer Centre
Emily S. Wong: Victor Chang Cardiac Research Institute
Sarah-Jane Dawson: Peter MacCallum Cancer Centre
Shalin H. Naik: The Walter and Eliza Hall Institute of Medical Research
Mark A. Dawson: Peter MacCallum Cancer Centre

Nature, 2022, vol. 601, issue 7891, 125-131

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-021-04206-7

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