Collapse of Telomere Homeostasis in Hematopoietic Cells Caused by Heterozygous Mutations in Telomerase Genes

Abstract

Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain telomere length with proliferation in vitro and with age in vivo. We performed a detailed study of the telomere length by flow FISH analysis in leukocytes from 835 healthy individuals and 60 individuals with reduced telomerase activity. Healthy individuals showed a broad range in average telomere length in granulocytes and lymphocytes at any given age. The average telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. Gender differences between leukocyte telomere lengths were observed for all cell subsets studied; interestingly, this trend could already be detected at birth. Heterozygous carriers for mutations in either the telomerase reverse transcriptase ( hTERT) or the telomerase RNA template ( hTERC) gene displayed striking and comparable telomere length deficits. Further, non-carrier relatives of such heterozygous individuals had somewhat shorter leukocyte telomere lengths than expected; this difference was most profound for granulocytes. Failure to maintain telomere homeostasis as a result of partial telomerase deficiency is thought to trigger cell senescence or cell death, eventually causing tissue failure syndromes. Our data are consistent with these statements and suggest that the likelihood of similar processes occurring in normal individuals increases with age. Our work highlights the essential role of telomerase in the hematopoietic system and supports the notion that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall telomere shortening, are nevertheless crucial to maintain telomere homeostasis with age.

Author Summary

Human blood cells all originate from a common precursor, the hematopoietic stem cell. Telomerase, the enzyme responsible for adding telomere repeats to chromosome ends, is active in human hematopoietic stem cells but appears unable to maintain a constant telomere length with age. We first document the telomere length of different blood cell subsets from 835 healthy individuals between birth and 100 years, to delineate the normal rate of telomere attrition with age. Telomere lengths of blood cells were found to be slightly longer in women than in men, from birth and throughout life. We then compared this reference data to the telomere length in similar blood cell subsets from individuals with reduced telomerase activity as a result of a mutation in one of the genes encoding telomerase and from their direct relatives. Strikingly short telomeres were found in telomerase-deficient individuals, consistent with their cellular pathology and disease susceptibility, and somewhat shorter telomeres than expected were found in cells of relatives with normal telomerase maintenance. Our data can be used as a reference for blood cell telomere length in studies of normal and accelerated aging.