Non-genetic determinants of malignant clonal fitness at single-cell resolution
Details
Publication Year 2022-12-08,Volume 601,Issue #7891,Page 125-131
Journal Title
Nature
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.
Publisher
NPG
WEHI Research Division(s)
Immunology
PubMed ID
34880496
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2022-03-04 01:43:16
Last Modified: 2022-03-04 01:44:00
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