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.

将癌细胞重新编程为诱导多能干细胞（iPSC）可以捕获整个癌症基因组，从而创建遗传上忠实的人类癌症模型。通过提供严格的遗传克隆条件，iPSC 建模还可以揭示癌症异质性的非遗传来源，并提供将它们与遗传来源分开研究的独特机会，正如我们最近在基于 iPSC 的急性髓系白血病 (AML) 模型中所展示的那样。来自 AML 患者的基因克隆 iPSC 在造血分化后繁殖，具有白血病干细胞 (LSC) 层次结构的所有特征，具有表型和功能异质性。在这里，我们讨论可以从 iPSC 建模中学到的有关 LSC 状态、其可塑性、稳定性以及遗传和表观遗传决定因素的经验教训。我们还讨论了利用 AML-iPSC 前瞻性分离大量 iLSC 以进行大规模实验（例如筛选）以及发现针对 AML LSC 的新治疗靶点的实际和转化意义。