Modeling Human Bone Marrow Failure Syndromes Using Pluripotent Stem Cells and Genome Engineering  Moonjung Jung, Cynthia E Dunbar, Thomas Winkler  Molecular Therapy  Volume 23, Issue 12, Pages 1832-1842 (December 2015) DOI: 10.1038/mt.2015.180 Copyright © 2015 American Society of Gene & Cell Therapy Terms and Conditions

Figure 1 iPSC disease modeling schema in bone marrow failure syndromes and challenges. Patient-specific iPSCs can be derived from terminally differentiated cells of patients. Any cell type could be used when modeling inherited BMFS with germ line mutation, but affected lineage, such as peripheral blood mononuclear cells (PB MNCs) or BM MNCs, should be chosen when modeling acquired BMFS, such as de novo myelodysplastic syndrome or inherited BMFS with variable penetrance. Both viral or nonviral, integrating or nonintegrating reprogramming vectors have been used to model BMFS. Nonintegrating vectors are favored when planning for cell therapy application to avoid potential insertional mutagenesis and malignant transformation. Once iPSCs have been derived from a patient, then hematopoietic differentiation may identify quantitative or qualitative defects in hematopoietic stem cell generation and/or maintenance. Hematopoietic defects may become more obvious when differentiated into lineage-committed cells. Gene correction mediated by ZFN, TALEN, or CRISPR/Cas9 will provide validation of the role of given mutation in hematopoietic development and also can be used for gene-corrected autologous cell therapy in the future. BM, bone marrow; BMFS, bone marrow failure syndromes; OSKM, OCT4, SOX2, KLF4 and MYC; CRISPR/Cas9, clustered regularly interspaced short palindromic repeats; EB, embryoid body; iPSC, induced pluripotent stem cell; PBMC, peripheral blood mononuclear cell; TALEN, transcription activator–like effector nuclease; ZFN, zinc finger nuclease. Molecular Therapy 2015 23, 1832-1842DOI: (10.1038/mt.2015.180) Copyright © 2015 American Society of Gene & Cell Therapy Terms and Conditions