Blood Cancer UK Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Blood Cancer UK Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Adv Biol Regul. 2024 Jan;91:100993. doi: 10.1016/j.jbior.2023.100993. Epub 2023 Sep 27.
Acquired myeloid malignancies are a spectrum of clonal disorders known to be caused by sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells, leading to their aberrant self-renewal and differentiation. The increasing use of induced pluripotent stem cell (iPSC) technology to study myeloid malignancies has helped usher a paradigm shift in approaches to disease modeling and drug discovery, especially when combined with gene-editing technology. The process of reprogramming allows for the capture of the diversity of genetic lesions and mutational burden found in primary patient samples into individual stable iPSC lines. Patient-derived iPSC lines, owing to their self-renewal and differentiation capacity, can thus be a homogenous source of disease relevant material that allow for the study of disease pathogenesis using various functional read-outs. Furthermore, genome editing technologies like CRISPR/Cas9 enable the study of the stepwise progression from normal to malignant hematopoiesis through the introduction of specific driver mutations, individually or in combination, to create isogenic lines for comparison. In this review, we survey the current use of iPSCs to model acquired myeloid malignancies including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), acute myeloid leukemia and MDS/MPN overlap syndromes. The use of iPSCs has enabled the interrogation of the underlying mechanism of initiation and progression driving these diseases. It has also made drug testing, repurposing, and the discovery of novel therapies for these diseases possible in a high throughput setting.
获得性髓系恶性肿瘤是一系列已知的克隆性疾病，其病因是造血干/祖细胞中遗传损伤的连续获得，导致其异常自我更新和分化。诱导多能干细胞（iPSC）技术在髓系恶性肿瘤研究中的广泛应用，推动了疾病建模和药物发现方法的范式转变，尤其是与基因编辑技术相结合时。重编程过程允许捕获原发性患者样本中发现的遗传损伤和突变负担的多样性，并将其转化为个体稳定的 iPSC 系。由于患者来源的 iPSC 系具有自我更新和分化能力，因此它们可以成为同质的疾病相关材料来源，可通过各种功能读数来研究疾病发病机制。此外，基因组编辑技术如 CRISPR/Cas9 可通过引入特定的驱动突变，单独或组合使用，逐步从正常造血向恶性造血进展，从而创建同基因系进行比较，来研究疾病的逐步进展。在这篇综述中，我们调查了 iPSC 用于建模获得性髓系恶性肿瘤的当前用途，包括骨髓增生异常综合征（MDS）、骨髓增殖性肿瘤（MPN）、急性髓系白血病和 MDS/MPN 重叠综合征。iPSC 的使用使我们能够探究这些疾病的起始和进展的潜在机制。它还使这些疾病的药物测试、重新利用和新型治疗方法的发现成为可能，实现了高通量设置。
