Title | Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Jones M, Osawa G, Regal JA, Weinberg DN, Taggart J, Kocak H, Friedman A, Ferguson DO, Keegan CE, Maillard I |
Journal | J Clin Invest |
Volume | 124 |
Issue | 1 |
Pagination | 353-66 |
Date Published | 2014 Jan |
ISSN | 1558-8238 |
Keywords | Animals, Apoptosis, Caspase 3, Caspase 7, Cells, Cultured, Chromosomal Instability, Chromosome Aberrations, Enzyme Activation, G2 Phase Cell Cycle Checkpoints, Genes, Lethal, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Liver, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Pancytopenia, Telomere Shortening, Telomere-Binding Proteins |
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. |
DOI | 10.1172/JCI67871 |
Alternate Journal | J. Clin. Invest. |
PubMed ID | 24316971 |
PubMed Central ID | PMC3967656 |
Grant List | AI091627 / AI / NIAID NIH HHS / United States P30-CA46592 / CA / NCI NIH HHS / United States P30 CA046592 / CA / NCI NIH HHS / United States R01 HD058606 / HD / NICHD NIH HHS / United States R01 AI091627 / AI / NIAID NIH HHS / United States GM07863 / GM / NIGMS NIH HHS / United States T32 HD007505 / HD / NICHD NIH HHS / United States R01 HL079118 / HL / NHLBI NIH HHS / United States T32 GM007863 / GM / NIGMS NIH HHS / United States HL079118 / HL / NHLBI NIH HHS / United States HD058606 / HD / NICHD NIH HHS / United States T32 CA009676 / CA / NCI NIH HHS / United States HD007505 / HD / NICHD NIH HHS / United States CA009676 / CA / NCI NIH HHS / United States T32 GM007315 / GM / NIGMS NIH HHS / United States |
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