Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Evaluation and Management of Hematopoietic Failure in Dyskeratosis Congenita.

ABSTRACT: Dyskeratosis congenita (DC) is a rare, inherited bone marrow failure (BMF) syndrome characterized by variable manifestations and ages of onset, and predisposition to cancer. DC is one of a spectrum of diseases caused by mutations in genes regulating telomere maintenance, collectively referred to as telomere biology disorders (TBDs). Hematologic disease is common in children with DC/TBD. Timely diagnosis of underlying TBD in patients with BMF affects treatment and has been facilitated by increased awareness and availability of diagnostic tests in recent years. This article summarizes the pathophysiology, evaluation, and management of hematopoietic failure in patients with DC and other TBDs.

SUBMITTER: Agarwal S

PROVIDER: S-EPMC7307713 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Evaluation and Management of Hematopoietic Failure in Dyskeratosis Congenita.

Agarwal Suneet S

Hematology/oncology clinics of North America 20180528 4

Dyskeratosis congenita (DC) is a rare, inherited bone marrow failure (BMF) syndrome characterized by variable manifestations and ages of onset, and predisposition to cancer. DC is one of a spectrum of diseases caused by mutations in genes regulating telomere maintenance, collectively referred to as telomere biology disorders (TBDs). Hematologic disease is common in children with DC/TBD. Timely diagnosis of underlying TBD in patients with BMF affects treatment and has been facilitated by increase ...[more]

PMID: 30047419

Similar Datasets

Dyskeratosis congenita.

Project description:Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized clinically by the triad of abnormal nails, reticular skin pigmentation, and oral leukoplakia, and is associated with high risk of developing aplastic anemia, myelodysplastic syndrome, leukemia, and solid tumors. Patients have very short germline telomeres, and approximately half have mutations in one of six genes encoding proteins that maintain telomere function. Accurate diagnosis of DC is critical to ensure proper clinical management, because patients who have DC and bone marrow failure do not respond to immunosuppressive therapy and may have increased morbidity and mortality associated with hematopoietic stem cell transplantation.

| S-EPMC2702847 | biostudies-literature

p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita.

Project description:Dyskeratosis congenita (DC) is a bone marrow failure syndrome associated with telomere dysfunction. The progression and molecular determinants of hematopoietic failure in DC remain poorly understood. Here, we use the directed differentiation of human embryonic stem cells harboring clinically relevant mutations in telomerase to understand the consequences of DC-associated mutations on the primitive and definitive hematopoietic programs. Interestingly, telomere shortening does not broadly impair hematopoiesis, as primitive hematopoiesis is not impaired in DC cells. In contrast, while phenotypic definitive hemogenic endothelium is specified, the endothelial-to-hematopoietic transition is impaired in cells with shortened telomeres. This failure is caused by DNA damage accrual and is mediated by p53 stabilization. These observations indicate that detrimental effects of telomere shortening in the hematopoietic system are specific to the definitive hematopoietic lineages. This work illustrates how telomere dysfunction impairs hematopoietic development and creates a robust platform for therapeutic discovery for treatment of DC patients.

| S-EPMC5550027 | biostudies-literature

Conditional TRF1 knockout in the hematopoietic compartment leads to bone marrow failure and recapitulates clinical features of dyskeratosis congenita.

Project description:TRF1 is part of the shelterin complex, which binds telomeres and it is essential for their protection. Ablation of TRF1 induces sister telomere fusions and aberrant numbers of telomeric signals associated with telomere fragility. Dyskeratosis congenita is characterized by a mucocutaneous triad, bone marrow failure (BMF), and presence of short telomeres because of mutations in telomerase. A subset of patients, however, show mutations in the shelterin component TIN2, a TRF1-interacting protein, presenting a more severe phenotype and presence of very short telomeres despite normal telomerase activity. Allelic variations in TRF1 have been found associated with BMF. To address a possible role for TRF1 dysfunction in BMF, here we generated a mouse model with conditional TRF1 deletion in the hematopoietic system. Chronic TRF1 deletion results in increased DNA damage and cellular senescence, but not increased apoptosis, in BM progenitor cells, leading to severe aplasia. Importantly, increased compensatory proliferation of BM stem cells is associated with rapid telomere shortening and further increase in senescent cells in vivo, providing a mechanism for the very short telomeres of human patients with mutations in the shelterin TIN2. Together, these results represent proof of principle that mutations in TRF1 lead to the main clinical features of BMF.

| S-EPMC3918664 | biostudies-literature

Cancer in dyskeratosis congenita.

Project description:Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome. The spectrum of cancer susceptibility in this disorder of telomere biology has not been described. There were more than 500 cases of DC reported in the literature from 1910 to 2008; the National Cancer Institute (NCI) prospective DC cohort enrolled 50 cases from 2002 to 2007. Sixty cancers were reported in 52 literature cases, while 7 occurred among patients in the NCI DC cohort. The 2 cohorts were comparable in their median overall survival (42 years) and cumulative incidence of cancer (40%-50% by age 50 years). The most frequent solid tumors were head and neck squamous cell carcinomas (40% of patients in either cohort), followed by skin and anorectal cancer. The ratio of observed to expected cancers (O/E ratio) in the NCI cohort was 11-fold compared with the general population (P < .05). Significantly elevated O/E ratios were 1154 for tongue cancer and 195 for acute myeloid leukemia. Survival after bone marrow transplantation for aplastic anemia or leukemia was poor in both cohorts. The frequency and types of cancer in DC are surpassed only by those in Fanconi anemia (FA), indicating that FA and DC have similarly high risks of adverse hematologic and neoplastic events, and patients with these diseases should be counseled and monitored similarly.

| S-EPMC2710915 | biostudies-literature

Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita.

Project description:Reduced levels of TERC, the telomerase RNA component, cause dyskeratosis congenita (DC) in patients harboring mutations in TERC, PARN, NOP10, NHP2, NAF1, or DKC1. Inhibition of the noncanonical poly(A) polymerase PAPD5, or the exosome RNA degradation complex, partially restores TERC levels in immortalized DKC1 mutant cells, but it remains unknown if modulation of posttranscriptional processing of TERC could improve hematopoietic output in DC. We used human embryonic stem cells (hESCs) with a common dyskerin mutation (DKC1_A353V), which have defective telomere maintenance and reduced definitive hematopoietic potential, to understand the effects of reducing EXOSC3 activity, or silencing PAPD5-mediated oligoadenylation, on hematopoietic progenitor specification and function in DC. Reduction of EXOSC3 or PAPD5 levels in DKC1 mutant hESCs led to functional improvements in TERC levels and telomerase activity, with concomitant telomere elongation and reduced levels of DNA damage signaling. Interestingly, the silencing of PAPD5, but not EXOSC3, significantly restored definitive hematopoietic potential in DKC1 mutant cells. Mechanistically, we show that PAPD5 inhibition is sustained in differentiated CD34+ cells, with a concomitant increase in mature, functional, forms of TERC, indicating that regulation of PAPD5 is a potential strategy to reverse hematologic dysfunction in DC patients.

| S-EPMC6428664 | biostudies-literature

Telomerase dysfunction and dyskeratosis congenita.

Project description:Dyskeratosis congenita (DC) is a multi system bone marrow failure syndrome characterized by muco-cutaneous abnormalities and an increased predisposition to malignancy. It exhibits considerable clinical and genetic heterogeneity. X-linked recessive, autosomal dominant and autosomal recessive forms of the disease are recognized. The X-linked recessive form is due to mutations in dyskerin, which is a component of both small nucleolar ribonuclear protein particles and the telomerase complex. Autosomal dominant DC is due to mutations in the RNA component of telomerase, TERC. As dyskerin and TERC are both components of the telomerase complex and all patients with DC have short telomeres it appears that the principal pathology in DC relates to telomerase dysfunction. The gene or genes involved in the recessive form of DC remain elusive, though genes whose products are required for telomere maintenance remain strong candidates. The study of DC has highlighted the critical role of telomerase and the consequences, including premature aging and malignancy, of its dysfunction.

| S-EPMC3449960 | biostudies-other

The genetics of dyskeratosis congenita.

Project description:Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome associated with characteristic mucocutaneous features and a variable series of other somatic abnormalities. The disease is heterogeneous at the genetic and clinical levels. Determination of the genetic basis of DC has established that the disease is caused by a number of genes, all of which encode products involved in telomere maintenance, either as part of telomerase or as part of the shelterin complex that caps and protects telomeres. There is overlap at the genetic and clinical levels with other, more common conditions, including aplastic anemia (AA), pulmonary fibrosis (PF), and liver cirrhosis. Although part of the spectrum of disorders known to be associated with DC, it has emerged that mutations in telomere maintenance genes can lead to the development of AA and PF in the absence of other DC features. Here we discuss the genetics of DC and its relationship to disease presentation.

| S-EPMC3269008 | biostudies-literature

Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1.

Project description:Dyskeratosis congenita (DC) is a rare telomere biology disorder, which results in different clinical manifestations, including severe bone marrow failure. To date, the only curative treatment for the bone marrow failure in DC patients is allogeneic hematopoietic stem cell transplantation. However, due to the toxicity associated to this treatment, improved therapies are recommended for DC patients. Here, we aimed at generating DC-like human hematopoietic stem cells in which the efficacy of innovative therapies could be investigated. Because X-linked DC is the most frequent form of the disease and is associated with an impaired expression of DKC1, we have generated DC-like hematopoietic stem cells based on the stable knock-down of DKC1 in human CD34+ cells with lentiviral vectors encoding for DKC1 short hairpin RNAs. At a molecular level, DKC1-interfered CD34+ cells showed a decreased expression of TERC, as well as a diminished telomerase activity and increased DNA damage, cell senescence, and apoptosis. Moreover, DKC1-interfered human CD34+ cells showed defective clonogenic ability and were incapable of repopulating the hematopoiesis of immunodeficient NSG mice. The development of DC-like hematopoietic stem cells will facilitate the understanding of the molecular and cellular basis of this inherited bone marrow failure syndrome and will serve as a platform to evaluate the efficacy of new hematopoietic therapies for DC.

| S-EPMC7844988 | biostudies-literature

Dyskeratosis congenita and telomere biology disorders.

Project description:Numerous genetic discoveries and the advent of clinical telomere length testing have led to the recognition of a spectrum of telomere biology disorders (TBDs) beyond the classic dyskeratosis congenita (DC) triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia occurring with pediatric bone marrow failure. Patients with DC/TBDs have very short telomeres for their age and are at high risk of bone marrow failure, cancer, pulmonary fibrosis (PF), pulmonary arteriovenous malformations, liver disease, stenosis of the urethra, esophagus, and/or lacrimal ducts, avascular necrosis of the hips and/or shoulders, and other medical problems. However, many patients with TBDs do not develop classic DC features; they may present in middle age and/or with just 1 feature, such as PF or aplastic anemia. TBD-associated clinical manifestations are progressive and attributed to aberrant telomere biology caused by the X-linked recessive, autosomal dominant, autosomal recessive, or de novo occurrence of pathogenic germline variants in at least 18 different genes. This review describes the genetics and clinical manifestations of TBDs and highlights areas in need of additional clinical and basic science research.

| S-EPMC9821046 | biostudies-literature

Accelerated hematopoietic stem cell aging in a mouse model of dyskeratosis congenita responds to antioxidant treatment.

Project description:Mutations in DKC1, encoding telomerase associated protein dyskerin, cause X-linked dyskeratosis congenita (DC), a bone marrow (BM) failure, and cancer susceptibility syndrome. Decreased accumulation of telomerase RNA resulting in excessive telomere shortening and premature cellular senescence is thought to be the primary cause of disease in X-linked DC. Affected tissues are those that require constant renewal by stem cell activity. We previously showed that in Dkc1(?15) mice, which contain a mutation that is a copy of a human mutation causing DC, mutant cells have a telomerase-dependent proliferative defect and increased accumulation of DNA damage in the first generation before the telomeres are short. We now demonstrate the presence of the growth defect in Dkc1(?15) mouse embryonic fibroblasts in vitro and show that accumulation of DNA damage and levels of reactive oxygen species increase with increasing population doublings. Treatment with the antioxidant, N-acetyl cysteine (NAC), partially rescued the growth disadvantage of mutant cells in vitro and in vivo. Competitive BM repopulation experiments showed that the Dkc1(?15) mutation is associated with a functional stem cell defect that becomes more severe with increasing age, consistent with accelerated senescence, a hallmark of DC hematopoiesis. This stem cell phenotype was partially corrected by NAC treatment. These results suggest that a pathogenic Dkc1 mutation accelerates stem cell aging, that increased oxidative stress might play a role in the pathogenesis of X-linked DC, and that some manifestations of DC may be prevented or delayed by antioxidant treatment.

| S-EPMC3238467 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data