获得性骨髓性恶性肿瘤是一系列克隆性疾病,已知是由造血干细胞和祖细胞中遗传病变的顺序获得引起的。导致他们异常的自我更新和分化。越来越多地使用诱导多能干细胞(iPSC)技术来研究骨髓恶性肿瘤,这有助于推动疾病建模和药物发现方法的范式转变。特别是与基因编辑技术相结合。重编程过程允许将原发性患者样品中发现的遗传损伤和突变负担的多样性捕获到个体稳定的iPSC系中。患者来源的iPSC线,由于他们的自我更新和分化能力,因此,可以是疾病相关材料的同质来源,其允许使用各种功能读出来研究疾病发病机理。此外,像CRISPR/Cas9这样的基因组编辑技术能够通过引入特定的驱动突变来研究从正常到恶性造血的逐步进展,单独或组合,创建等基因线进行比较。在这次审查中,我们调查了目前使用iPSCs来模拟获得性髓系恶性肿瘤,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的使用使得能够询问驱动这些疾病的起始和进展的潜在机制。它还进行了药物测试,重新利用,以及在高通量环境中发现这些疾病的新疗法。
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.