Abstract
Cancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with it the ability to eradicate cancer at its source. In acute myeloid leukemia (AML), leukemic stem cells (LSCs) underlie mortality but are difficult to isolate due to their low abundance and high similarity to healthy hematopoietic stem cells (HSCs). Here, we demonstrate that LSCs, HSCs, and pre-leukemic stem cells can be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants. While mutational status discriminates between healthy and cancerous cells, gene expression distinguishes stem cells and progenitor cell populations. Our approach enables the identification of LSC-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations. Taken together, we demonstrate the power of single-cell multi-omic approaches in characterizing cancer stem cells.
Highlights
Cancer stem cells drive disease progression and relapse in many types of cancer
Cancer stem cells (CSCs), residing at the top of the hierarchy, are able to fuel long-term cancer growth and drive relapse, whereas the bulk of the cancer consists of rapidly dividing cells with limited capacity for self-renewal, i.e., cells that exhaust their replicative potential after a finite number of divisions[2,3,4]
Pre-leukemic stem cells (LSCs) are thought to typically carry mutations associated with Clonal Hematopoiesis of Indeterminate Potential (CHIP) but not mutations associated with leukemia[7,20,21], potentially enabling their identification by profiling both known leukemic and known preleukemic mutations
Summary
Cancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with it the ability to eradicate cancer at its source. In 10–20% of healthy individuals over age 70, the acquisition of pre-leukemic mutations in hematopoietic stem cells (HSCs) results in the dominance of a small number of HSC-derived clones, a process termed Clonal Hematopoiesis of Indeterminate Potential (CHIP)[6,7]. While such preleukemic stem cells (pre-LSCs) are capable of giving rise to healthy blood and immune cells, additional mutations can cause a complete block in differentiation and thereby result in the malignant expansion of aberrant progenitor cells[8]. The application of these methods to characterize LSCs has not been demonstrated, and in particular requires the ability to reliably detect clonal expansion events, associate clinically relevant coding mutations to clones with high confidence, and draw statements on gene expression changes between clones
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