Kotini Andriana G, Chang Chan-Jung, Chow Arthur, Yuan Han, Ho Tzu-Chieh, Wang Tiansu, Vora Shailee, Solovyov Alexander, Husser Chrystel, Olszewska Malgorzata, Teruya-Feldstein Julie, Perumal Deepak, Klimek Virginia M, Spyridonidis Alexandros, Rampal Raajit K, Silverman Lewis, Reddy E Premkumar, Papaemmanuil Elli, Parekh Samir, Greenbaum Benjamin D, Leslie Christina S, Kharas Michael G, Papapetrou Eirini P
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cell Stem Cell. 2017 Mar 2;20(3):315-328.e7. doi: 10.1016/j.stem.2017.01.009. Epub 2017 Feb 16.
Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9 and that this iPSC-based approach can be used to uncover disease-stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions.
髓系恶性肿瘤越来越被视为一种疾病谱，包括一系列造血疾病，这些疾病跨越了从克隆性造血到骨髓增生异常综合征（MDS）和急性髓系白血病（AML）的表型连续体。在本研究中，我们获得了一组诱导多能干细胞（iPSC）系，涵盖了一系列疾病阶段，包括白血病前期、低危MDS、高危MDS和继发性AML。在它们分化后，我们发现了严重程度分级和/或阶段特异性的造血表型，这些表型共同描绘了疾病进展的表型路线图，最终导致可连续移植的白血病。我们还表明，使用CRISPR/Cas9进行基因校正或引入突变，可以在该系统中模拟疾病阶段的转变，包括逆转和进展，并且这种基于iPSC的方法可用于揭示疾病阶段特异性的药物反应。因此，我们的研究为界定髓系转化起始和进展的细胞事件提供了见解，并为测试基因和药物干预提供了一个新平台。
