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

Fennell, KA; Vassiliadis, D; Lam, EYN; Martelotto, LG; Balic, JJ; Hollizeck, S; Weber, TS; Semple, T; Wang, Q; Miles, DC; MacPherson, L; Chan, YC; Guirguis, AA; Kats, LM; Wong, ES; Dawson, SJ; Naik, SH; Dawson, MA

Author(s): Fennell, KA; Vassiliadis, D; Lam, EYN; Martelotto, LG; Balic, JJ; Hollizeck, S; Weber, TS; Semple, T; Wang, Q; Miles, DC; MacPherson, L; Chan, YC; Guirguis, AA; Kats, LM; Wong, ES; Dawson, SJ; Naik, SH; Dawson, MA;
Details: Publication Year 2022-01,Volume 601,Issue #7891,Page 125-131
Journal Title: Nature
Publication Type: Research article
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.
Keywords: Animals; *Cell Competition/drug effects; Cell Line; Cell Lineage/drug effects; Clone Cells/drug effects/metabolism/*pathology; Female; Humans; Leukemia, Myeloid, Acute/drug therapy/genetics/*pathology; Mice; Mice, Inbred C57BL; Secretory Leukocyte Peptidase Inhibitor/metabolism; *Single-Cell Analysis
Department(s): Laboratory Research; Medical Oncology; Haematology
PubMed ID: 34880496
Publisher's Version: https://doi.org/10.1038/s41586-021-04206-7
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-24 05:32:24

Last Modified: 2024-10-24 05:33:22