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Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation
Morgan Jones, … , Catherine E. Keegan, Ivan Maillard
Morgan Jones, … , Catherine E. Keegan, Ivan Maillard
Published December 9, 2013
Citation Information: J Clin Invest. 2014;124(1):353-366. https://doi.org/10.1172/JCI67871.
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Research Article Hematology

Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

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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.

Authors

Morgan Jones, Gail Osawa, Joshua A. Regal, Daniel N. Weinberg, James Taggart, Hande Kocak, Ann Friedman, David O. Ferguson, Catherine E. Keegan, Ivan Maillard

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Figure 6

Complete Acd inactivation in fetal hematopoietic cells is incompatible with survival.

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Complete Acd inactivation in fetal hematopoietic cells is incompatible w...
(A) Experimental design: Acd inactivation restricted to fetal hematopoiesis was achieved using a Vav-Cre+ transgene. Breedings were established using Vav-Cre+Acdfl/+ parents. (B) At E14.5, live Vav-Cre+Acdfl/fl fetuses could be identified, however, these mice were pale compared with those of all other genotypes. (C) Flow cytometric analysis of E14.5 fetal livers demonstrating that Vav-Cre+Acdfl/fl fetuses had profoundly depleted Lin–Sca-1+cKithi (LSK) hematopoietic progenitors. Representative flow cytometry plots are shown. Numbers indicate the percentage of cells in each gate.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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