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Cited by 18Telomeres, Telomerase, and SenescenceHematopoietic Stem Cell TransplantationBlood disorders and treatments

Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

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Jones, Morgan, Osawa, Gail, Regal, Joshua A., Weinberg, Daniel N., Taggart, James, Kocak, Hande, Friedman, Ann, Ferguson, David O. +2 more·2014·Journal of Clinical Investigation
DOI 10.1172/jci67871PMC PMC3967656
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Abstract

The shelterin complex plays dual functions in telomere homeostasis by recruiting telomerase and preventing the activation of a DNA damage response at telomeric ends. Somatic stem cells require telomerase activity, as evidenced by progressive stem cell loss leading to bone marrow failure in hereditary dyskeratosis congenita. Recent work demonstrates that dyskeratosis congenita can also arise from mutations in specific shelterin genes, although little is known about shelterin functions in somatic stem cells. We found that mouse hematopoietic stem cells (HSCs) are acutely sensitive to inactivation of the shelterin gene Acd, encoding TPP1. Homozygosity for a hypomorphic acd allele preserved the emergence and expansion of fetal HSCs but led to profoundly defective function in transplantation assays. Upon complete Acd inactivation, HSCs expressed p53 target genes, underwent cell cycle arrest, and were severely depleted within days, leading to hematopoietic failure. TPP1 loss induced increased telomeric fusion events in bone marrow progenitors. However, unlike in epidermal stem cells, p53 deficiency did not rescue TPP1-deficient HSCs, indicating that shelterin dysfunction has unique effects in different stem cell populations. Because the consequences of telomere shortening are progressive and unsynchronized, acute loss of shelterin function represents an attractive alternative for studying telomere crisis in hematopoietic progenitors.

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  • Patients with dyskeratosis congenita have mutations in DKC1, and defects in telomere maintenance lead to telomere deprotection and HSC failure to sustain bone marrow reconstituting activity.

    “patients with dyskeratosis congenita have mutations in the DKC1 gene, an important component of the telomerase complex191. Defects in telomere maintainance lead to deprotection of telomeres and, in HSCs, cause failure to sustain bone marrow reconstituting activity192.”

    From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [192]

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Cited by

Sorted by citations

Authors
Jones, M., Osawa, G., Regal, J. A., Weinberg, D. N., Taggart, J., Kocak, H., Friedman, A., Ferguson, D. O., Keegan, C. E., & Maillard, I.
Affiliations
  • Life Sciences Institute (SG)
  • University of Michigan (US)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2013-12-09
Volume
124
Issue
1
Pages
353-366
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci67871
PMC
PMC3967656
OpenAlex
W1966891756
Cited by
18
References
11
Citations by year
2023: 3 · 2022: 1 · 2021: 1 · 2020: 2 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 3
FWCI
1.62
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of Pennsylvania
  • University of Michigan (48109)
  • National Institutes of Health (CA46592)
  • Directorate for Biological Sciences
  • College of Pharmacy, University of Michigan
  • National Heart, Lung, and Blood Institute (R01HL079118, HL079118)
  • National Cancer Institute (P30-CA 46592, CA009676, P30CA046592, T32CA009676)
  • National Institute of General Medical Sciences (GM 07863, T32GM007863, T32GM007315)
  • National Institute of Allergy and Infectious Diseases (AI091627, R01AI091627)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD058606, HD058606, T32HD007505, HD007505)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
Keywords
hematopoietic stem cells, shelterin complex, TPP1, telomere homeostasis, telomerase, dyskeratosis congenita, p53 target genes, telomeric fusions, hematopoietic failure, telomere crisis, bone marrow progenitor cells, stem cell depletion
MeSH terms
Animals, Cells, Cultured, Chromosome Aberrations, Enzyme Activation, Genes, Lethal, Hematopoietic Stem Cells, Liver, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Pancytopenia, Apoptosis, Hematopoietic Stem Cell Transplantation, Telomere-Binding Proteins, Chromosomal Instability, Mice, Caspase 3, Caspase 7, Telomere Shortening, G2 Phase Cell Cycle Checkpoints

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