"Stem cell" origin of the hematopoietic defect in dyskeratosis congenita

Abstract

We have used the long-term bone marrow culture (LTBMC) system to analyze hematopoiesis in three patients with dyskeratosis congenita (DC), two of whom had aplastic anemia, and the third had a normal blood count (apart from mild macrocytosis) and normal BM cellularity. Hematopoiesis was severely defective in all three patients, as measured by a low incidence of colony-forming cells and a low level of hematopoiesis in LTBMC. The function of the marrow stroma was normal in its ability to support the growth of hematopoietic progenitors from normal marrows seeded onto them in all three cases, but the generation of hematopoietic progenitors from patients marrow cells inoculated onto normal stromas was reduced, thus suggesting the defect to be of stem cell origin. The parents and unaffected brother of one of the families have also been studied in LTBMC and all showed normal hematopoietic and stromal cell function. From this study we speculate that there are some similarities between DC and the defect in the W/Wv mouse.

Exogenous TERC alone can enhance proliferative potential, telomerase activity and telomere length in lymphocytes from dyskeratosis congenita patients

“…The majority of DC patients will have developed BM failure by 30 years of age and this is the principal cause of mortality . DC has been shown to have a stem and progenitor cell defect (Colvin et al, 1984;Friedland et al, 1985;Marsh et al, 1992;Goldman et al, 2008;Kirwan et al, 2008) and the hypothesis that many of the clinical features can be explained by premature cell death and/or senescence is consistent with the observed bone marrow failure and reduced numbers of peripheral blood progenitors.…”

Advances in the understanding of dyskeratosis congenita

“…As haemopoietic cells, marrow stromal cells, endothelial cells and dermis all originate from the primitive mesoderm it is easy to see how mutations affecting these primitive cells can lead to the two dissimilar aspects of the disease. Early studies have shown that there is a reduction or absence of the multi-lineage colony-forming cells in patients with DC (Colvin et al, 1984;Marsh et al, 1992;Yamaguchi et al, 2005), and more recently these have been shown to differ according to the mutation involved i.e. patients with DKC1 mutations have a reduction in colony number whereas patients with mutations in TERC tend have no detectable colonies in the peripheral blood (Kirwan et al, 2008a).…”

Dyskeratosis congenita: a genetic disorder of many faces

“…Telomerase expression is usually low or absent in most somatic tissues but it is believed that telomerase activity is upregulated in stem cells and germ cells to allow the telomere to be renewed, ensuring that cells with a high cellular turnover remain viable (12). DC has been shown to have a stem and/or progenitor cell defect (13)(14)(15) and it is believed that telomerase deficiency results in accelerated telomere shortening in DC cells and a consequent increased loss of cells particularly from tissues which need constant renewal, such as the haematopoietic and dermatological systems so prominently affected in DC (16,17). X-linked recessive, autosomal dominant (AD) and autosomal recessive (AR) forms of the disease are recognized (18) and, in general, the X-linked recessive form appears to be associated with a more severe phenotype compared with the AD form.…”