PMID:23585473

Citation	Winkler, T, Hong, SG, Decker, JE, Morgan, MJ, Wu, C, Hughes, WM 5th, Yang, Y, Wangsa, D, Padilla-Nash, HM, Ried, T, Young, NS, Dunbar, CE and Calado, RT (2013) Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs. J. Clin. Invest. 123:1952-63
Abstract	Critically short telomeres activate p53-mediated apoptosis, resulting in organ failure and leading to malignant transformation. Mutations in genes responsible for telomere maintenance are linked to a number of human diseases. We derived induced pluripotent stem cells (iPSCs) from 4 patients with aplastic anemia or hypocellular bone marrow carrying heterozygous mutations in the telomerase reverse transcriptase (TERT) or the telomerase RNA component (TERC) telomerase genes. Both mutant and control iPSCs upregulated TERT and TERC expression compared with parental fibroblasts, but mutant iPSCs elongated telomeres at a lower rate compared with healthy iPSCs, and the deficit correlated with the mutations' impact on telomerase activity. There was no evidence for alternative lengthening of telomere (ALT) pathway activation. Elongation varied among iPSC clones derived from the same patient and among clones from siblings harboring identical mutations. Clonal heterogeneity was linked to genetic and environmental factors, but was not influenced by residual expression of reprogramming transgenes. Hypoxia increased telomere extension in both mutant and normal iPSCs. Additionally, telomerase-mutant iPSCs showed defective hematopoietic differentiation in vitro, mirroring the clinical phenotype observed in patients and demonstrating that human telomere diseases can be modeled utilizing iPSCs. Our data support the necessity of studying multiple clones when using iPSCs to model disease.
Links	PubMed PMC3635755 Online version:10.1172/JCI67146
Keywords	Anemia, Aplastic/metabolism; Animals; Cell Differentiation; DNA Mutational Analysis; Environment; Fibroblasts/cytology; Hematopoiesis/physiology; Hematopoietic Stem Cells/cytology; Humans; Immunohistochemistry; Induced Pluripotent Stem Cells/cytology; Leukocytes/cytology; Mice; Mutation; Phenotype; Telomerase/metabolism; Telomere/ultrastructure; Transgenes
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:TERT		GO:0060218: hematopoietic stem cell differentiation	ECO:0000315:		P		Telomerase-mutant ipscs caused impaired hematopoietic differentiation in vitro. Ref to figure 6	complete CACAO 9530

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