Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

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.

Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1

“…homozygous for the acd allele are profoundly defective in transplantation assays, and complete inactivation of Tpp1 results in severe depletion of hematopoietic progenitors (Jones et al 2014). Deletion of Tpp1 in the epithelial tissue leads to perinatal death, severe skin hyperpigmentation, defective hair follicle morphogenesis, and epithelial dysplasia (Tejera et al 2010).…”

Stem cell aging: mechanisms, regulators and therapeutic opportunities

“…Finally, patients with dyskeratosis congenita have mutations in the DKC1 gene, an important component of the telomerase complex 191 . Defects in telomere maintainance lead to deprotection of telomeres and, in HSCs, cause failure to sustain bone marrow reconstituting activity 192 .…”

The shelterin complex and hematopoiesis

“…We recently demonstrated that Acd critically regulates HSC homeostasis (39). In mice with hypomorphic acd alleles, we observed G2/M arrest in fetal hematopoietic progenitors.…”

“…This profound in vivo significance is most prevalent in tissues that require active turnover and robust stem cell compartments, such as hematopoietic tissues. In addition to developmental defects, several mouse models of shelterin dysfunction revealed features reminiscent of the human syndrome dyskeratosis congenita (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45).…”