The reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) can capture entire cancer genomes, and thus create genetically faithful models of human cancers. By providing stringent genetically clonal conditions, iPSC modeling can also unveil non-genetic sources of cancer heterogeneity and provide a unique opportunity to study them separately from genetic sources, as we recently showed in an iPSC-based model of acute myeloid leukemia (AML). Genetically clonal iPSCs, derived from a patient with AML, reproduce, upon hematopoietic differentiation, phenotypic and functional heterogeneity with all the hallmarks of a leukemia stem cell (LSC) hierarchy. Here we discuss the lessons that can be learned about the LSC state, its plasticity, stability and genetic and epigenetic determinants from iPSC modeling. We also discuss the practical and translational implications of exploiting AML-iPSCs to prospectively isolate large numbers of iLSCs for large-scale experiments, such as screens, and for discovery of new therapeutic targets specific to AML LSCs.
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