Sergei Doulatov1,2,3, Eirini P Papapetrou4,5,6,7. 1. Division of Hematology, Department of Medicine. 2. Department of Genome Sciences. 3. Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington. 4. Department of Oncological Sciences. 5. Department of Medicine. 6. Tisch Cancer Institute. 7. Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Abstract
PURPOSE OF REVIEW: Myeloid malignancies comprise a spectrum of genetically heterogeneous disorders marked by the stepwise acquisition of somatic mutations and clonal evolution. The blood and bone marrow of patients typically consists of a mix of different clones and subclones along the path of clonal evolution that cannot be deconvoluted with most current approaches. Here, we review the application of induced pluripotent stem cell (iPSC) technology to the study of the clonal architecture and clonal evolution of these diseases, focusing on myelodysplastic syndromes and acute myeloid leukemia. RECENT FINDINGS: Reprogramming to pluripotency allows capture of the genomes of single somatic cells into stable iPSC lines. In addition, precise genome editing can introduce specific driver mutations, isolated, and in combinations, into normal iPSCs. Studies utilizing these approaches have elucidated the clonal composition and mutational order in patients with myeloid neoplasms. Importantly, they have also enabled functional interrogation of the cellular and molecular consequences of individual mutations and their combinations and allowed testing of the effects of drugs on distinct disease clones. SUMMARY: Human iPSCs are important tools to elucidate the mechanisms of progression from normal to malignant haematopoiesis and empower drug testing and drug discovery.
PURPOSE OF REVIEW: Myeloid malignancies comprise a spectrum of genetically heterogeneous disorders marked by the stepwise acquisition of somatic mutations and clonal evolution. The blood and bone marrow of patients typically consists of a mix of different clones and subclones along the path of clonal evolution that cannot be deconvoluted with most current approaches. Here, we review the application of induced pluripotent stem cell (iPSC) technology to the study of the clonal architecture and clonal evolution of these diseases, focusing on myelodysplastic syndromes and acute myeloid leukemia. RECENT FINDINGS: Reprogramming to pluripotency allows capture of the genomes of single somatic cells into stable iPSC lines. In addition, precise genome editing can introduce specific driver mutations, isolated, and in combinations, into normal iPSCs. Studies utilizing these approaches have elucidated the clonal composition and mutational order in patients with myeloid neoplasms. Importantly, they have also enabled functional interrogation of the cellular and molecular consequences of individual mutations and their combinations and allowed testing of the effects of drugs on distinct disease clones. SUMMARY: Human iPSCs are important tools to elucidate the mechanisms of progression from normal to malignant haematopoiesis and empower drug testing and drug discovery.