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

• Published in: Nature (London) Vol. 601; no. 7891; pp. 125 - 131
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.01.2022; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/31; 38/22; 38/35; 38/39; 38/77; 45/23; 45/29; 631/337/2019; 631/67/1990/283; 631/67/2329; 631/67/71; 64/60; Acute myeloid leukemia; Animal models; Animals; Antigen presentation; Antigens; Cancer; Cell Competition - drug effects; Cell Line; Cell Lineage - drug effects; Chemotherapy; Clonal selection; Clone Cells - drug effects; Clone Cells - metabolism; Clone Cells - pathology; Cloning; Competition; Female; Fitness; Gene expression; Genotype & phenotype; Hematopoietic stem cells; Heterogeneity; Humanities and Social Sciences; Humans; Influence; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Leukocytes; Mice; Mice, Inbred C57BL; Microenvironments; Minimal residual disease; multidisciplinary; Mutation; Peptidase; Peptidases; Reproductive fitness; Science; Science (multidisciplinary); Secretory Leukocyte Peptidase Inhibitor - metabolism; Single-Cell Analysis; Stem cell transplantation; Stem cells; Transcription; Transplants & implants; Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-021-04206-7

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. Non-genetic malignant clonal dominance is a cell-intrinsic and heritable property that underpins clonal output and response to therapy in cancer.