Myeloid

Epigenetics

Gene

Stem cell

Genetic heterogeneity

Biology

Phenotype

Immunology

Genetics

clone (Java method)

Somatic evolution in cancer

Haematopoiesis

Nature

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&nbsp;secretory leukocyte peptidase inhibitor&nbsp;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&nbsp;immune microenvironments and in the context of clonal competition between genetica...

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