Medical College of Wisconsin
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Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs. J Clin Invest 2013 May;123(5):1952-63

Date

04/16/2013

Pubmed ID

23585473

Pubmed Central ID

PMC3635755

DOI

10.1172/JCI67146

Scopus ID

2-s2.0-84877105959 (requires institutional sign-in at Scopus site)   63 Citations

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.

Author List

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, Calado RT

Author

Jake E. Decker MD Assistant Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anemia, Aplastic
Animals
Cell Differentiation
DNA Mutational Analysis
Environment
Fibroblasts
Hematopoiesis
Hematopoietic Stem Cells
Humans
Immunohistochemistry
Induced Pluripotent Stem Cells
Leukocytes
Mice
Mutation
Phenotype
Telomerase
Telomere
Transgenes