Induced pluripotent stem cell-based modelling of disease evolution in myeloid leukemia: MDS to AML

The myelodysplastic syndromes (MDS) are common myeloid malignancies that develop from the successive acquisition of driver mutations in hematopoietic stem cells residing in the bone marrow. Around a third of MDS patients will develop secondary acute myeloid leukemia (sAML) and patients with high-risk MDS or sAML have a dismal prognosis. The study of disease progression in myeloid malignancy has been enhanced in recent years by the use of induced pluripotent stem cells (iPSCs) technology. iPSCs offer the advantage of indefinite expansion and the potential for genetic modification, with reprogramming enabling the capture of the full complement of genetic lesions found in primary patient bone marrow samples. The power of iPSC and CRISPR-Cas9 gene editing technologies have been harnessed to generate a range of iPSC-based cellular models of MDS, reflecting the genetic and biologic heterogeneity of the disease. Stage-specific patient iPSC lines have been produced and sequential gene editing in normal human iPSCs has been performed to map the evolution of MDS to AML. These studies have increased our understanding of the impact of driver mutations, and co-mutations, on disease phenotype and revealed mechanisms underlying disease stage transitions in myeloid malignancy. iPSC-based models of MDS have also proven important tools in high throughput drug screening and have empowered drug testing and drug discovery, offering a new platform to develop personalized therapy.