Spyrou Nikolaos, Papapetrou Eirini P
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Stem Cell Res. 2020 Dec 10;50:102117. doi: 10.1016/j.scr.2020.102117.
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.
将癌细胞重编程为诱导多能干细胞（iPSC）能够捕获完整的癌症基因组，从而创建忠实反映人类癌症基因特征的模型。通过提供严格的基因克隆条件，iPSC建模还能够揭示癌症异质性的非遗传来源，并提供一个独特的机会，将其与遗传来源分开进行研究，正如我们最近在一个基于iPSC的急性髓系白血病（AML）模型中所展示的那样。源自一名AML患者的基因克隆iPSC在造血分化时会重现具有白血病干细胞（LSC）层级所有特征的表型和功能异质性。在此，我们讨论从iPSC建模中可以学到的关于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前瞻性地分离大量iLSC用于大规模实验（如筛选）以及发现AML LSC特异性新治疗靶点的实际应用和转化意义。
