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British Journal of Haematology Dec 2023Individuals with telomere biology disorders (TBDs) have very short telomeres, high risk of bone marrow failure (BMF), and reduced survival. Using data from TBD patients,...
Individuals with telomere biology disorders (TBDs) have very short telomeres, high risk of bone marrow failure (BMF), and reduced survival. Using data from TBD patients, a mean leukocyte Southern blot telomere length (TL) of 5 kilobases (kb) was estimated as the 'telomere brink' at which human survival is markedly reduced. However, the shortest telomere, not the mean TL, signals replicative senescence. We used the Telomere Shortest Length Assay (TeSLA) to tally TL of all 46 chromosomes in blood-derived DNA and examined its relationship with TBDs. Patients (n = 18) had much shorter mean TL (TeSmTL) (2.54 ± 0.41 kb vs. 4.48 ± 0.52 kb, p < 0.0001) and more telomeres <3 kb than controls (n = 22) (70.43 ± 8.76% vs. 33.05 ± 6.93%, p < 0.0001). The proportion of ultrashort telomeres (<1.6 kb) was also higher in patients than controls (39.29 ± 10.69% vs. 10.40 ± 4.09%, p < 0.0001). TeS <1.6 kb was associated with severe (n = 11) compared with non-severe (n = 7) BMF (p = 0.027). Patients with multi-organ manifestations (n = 10) had more telomeres <1.6 kb than those with one affected organ system (n = 8) (p = 0.029). Findings suggest that TBD clinical manifestations are associated with a disproportionately higher number of haematopoietic cell telomeres reaching a telomere brink, whose length at the single telomere level is yet to be determined.
Topics: Humans; Biology; Bone Marrow Failure Disorders; Dyskeratosis Congenita; Pancytopenia; Telomere; Telomere Shortening
PubMed: 37354000
DOI: 10.1111/bjh.18945 -
GeroScience Aug 2023Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure....
Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null (Tert) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.
Topics: Humans; Animals; Mice; NAD; Telomere; Dyskeratosis Congenita; Inflammation; Hematopoietic Stem Cell Transplantation
PubMed: 36826621
DOI: 10.1007/s11357-023-00752-2 -
Genetic Counseling and Family Screening Recommendations in Patients with Telomere Biology Disorders.Current Hematologic Malignancy Reports Dec 2023Telomere biology disorders (TBDs) encompass a spectrum of genetic diseases with a common pathogenesis of defects in telomerase function and telomere maintenance causing... (Review)
Review
PURPOSE OF REVIEW
Telomere biology disorders (TBDs) encompass a spectrum of genetic diseases with a common pathogenesis of defects in telomerase function and telomere maintenance causing extremely short telomere lengths. Here, we review the current literature surrounding genetic testing strategies, cascade testing, reproductive implications, and the role of genetic counseling.
RECENT FINDINGS
The understanding of the genetic causes and clinical symptoms of TBDs continues to expand while genetic testing and telomere length testing are nuanced tools utilized in the diagnosis of this condition. Access to genetic counseling is becoming more abundant and is valuable in supporting patients and their families in making informed decisions. Patient resources and support groups are valuable to this community. Defining which populations should be offered genetic counseling and testing is imperative to provide proper diagnoses and medical management for not only the primary patient, but also their biological relatives.
Topics: Humans; Genetic Counseling; Telomere; Telomerase; Genetic Testing; Mutation
PubMed: 37787873
DOI: 10.1007/s11899-023-00713-8 -
European Journal of Haematology Sep 2023Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to...
BACKGROUND
Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes.
OBJECTIVE
To describe the outcome of TBD patients transplanted for marrow failure.
STUDY DESIGN
This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019.
RESULTS
The median age at transplantation was 14 years (range, 3-30 years). Most patients received a RIC regimen (n = 28) and bone marrow (BM) from an unrelated donor (n = 16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20 days (13-36 days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6 years; 1.4-19 years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p = .05; CI = 95%). Overall, 15 patients died after HCT, most of them (n = 11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD.
CONCLUSIONS
Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Retrospective Studies; Cohort Studies; Graft vs Host Disease; Unrelated Donors; Telomere; Biology; Transplantation Conditioning
PubMed: 37259830
DOI: 10.1111/ejh.14023 -
American Journal of Human Genetics Jun 2024
PubMed: 38866021
DOI: 10.1016/j.ajhg.2024.05.022 -
Archives of Dermatological Research May 2024Skin cancers are associated with a large number of genodermatoses. Existing knowledge and guidelines on the presentations of these genodermatoses focus... (Review)
Review
Skin cancers are associated with a large number of genodermatoses. Existing knowledge and guidelines on the presentations of these genodermatoses focus disproportionately on White patients. Our goal is to identify notable characteristics in location, frequency, and severity of cutaneous findings along with the median age of skin cancers in skin-of-color (SOC) patients with skin-cancer-associated genodermatoses to improve diagnosis rates. We searched for genodermatoses on six databases. Each case report or case series was reviewed, including reports, published in English, containing adult patient descriptions. Duplicate manuscripts were removed using EndNote. The following case-level data were collected from the manuscripts: age, gender, patient country or region of origin, author country/continent of residence, skin cancer-related, and other key dermatologic features. 381 published articles, with a total of 578 SOC patients, met criteria for inclusion. SOC patients can present with fewer classic findings, such as a lower incidence of basal cell carcinomas (44%) in SOC Gorlin syndrome patients than palmar pits (66%) and mandibular cysts (66%). Differences between SOC populations were also noted, such as leukoplakia being more common in Asian dyskeratosis congenita patients (80%) in comparison to African dyskeratosis congenita patients (44%). SOC patients also have varying onset of skin cancer depending on the genodermatosis, from a median of 25 years of age in Rothmund-Thomson syndrome to 53 in Muir-Torre syndrome. In this review, SOC patients with genodermatoses can have varying presentations. Being cognizant of these characteristics may lead to earlier diagnosis and interventions to mitigate skin-cancer-related morbidity in SOC patients.
Topics: Female; Humans; Male; Carcinoma, Basal Cell; Skin; Skin Diseases, Genetic; Skin Neoplasms; Racial Groups
PubMed: 38796611
DOI: 10.1007/s00403-024-03087-w -
Disease Models & Mechanisms Oct 2023p53 (encoded by Trp53) is a tumor suppressor, but mouse models have revealed that increased p53 activity may cause bone marrow failure, likely through dimerization...
p53 (encoded by Trp53) is a tumor suppressor, but mouse models have revealed that increased p53 activity may cause bone marrow failure, likely through dimerization partner, RB-like, E2F4/E2F5 and MuvB (DREAM) complex-mediated gene repression. Here, we designed a systematic approach to identify p53-DREAM pathway targets, the repression of which might contribute to abnormal hematopoiesis. We used Gene Ontology analysis to study transcriptomic changes associated with bone marrow cell differentiation, then chromatin immunoprecipitation-sequencing (ChIP-seq) data to identify DREAM-bound promoters. We next created positional frequency matrices to identify evolutionary conserved sequence elements potentially bound by DREAM. The same approach was developed to find p53-DREAM targets associated with brain abnormalities, also observed in mice with increased p53 activity. Putative DREAM-binding sites were found for 151 candidate target genes, of which 106 are mutated in a blood or brain genetic disorder. Twenty-one DREAM-binding sites were tested and found to impact gene expression in luciferase assays, to notably regulate genes mutated in dyskeratosis congenita (Rtel1), Fanconi anemia (Fanca), Diamond-Blackfan anemia (Tsr2), primary microcephaly [Casc5 (or Knl1), Ncaph and Wdr62] and pontocerebellar hypoplasia (Toe1). These results provide clues on the role of the p53-DREAM pathway in regulating hematopoiesis and brain development, with implications for tumorigenesis.
Topics: Animals; Mice; Brain; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p21; Promoter Regions, Genetic; Tumor Suppressor Protein p53
PubMed: 37661832
DOI: 10.1242/dmm.050376 -
Hematology. American Society of... Dec 2023Inherited bone marrow failure syndromes (IBMFS) encompass a group of rare genetic disorders characterized by bone marrow failure, non-hematologic multisystemic...
Inherited bone marrow failure syndromes (IBMFS) encompass a group of rare genetic disorders characterized by bone marrow failure, non-hematologic multisystemic comorbidities, disease defining congenital anomalies, and a susceptibility to myelodysplastic syndrome, acute myeloid leukemia, and in some instances solid tumors. The most common IBMFS include Fanconi anemia, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and telomere biology disorders/ dyskeratosis congenita. Allogeneic hematopoietic stem cell transplant (HCT) is a well-established curative treatment to correct the hematological manifestations but does not halt or reverse the nonhematological complications and may hasten them. With advances in HCT and in our ability to care for patients with IBMFS, an increasing number of survivors are making it imperative to not only diagnose but also treat late effects from the pre-, peri-, and post-HCT course and complications relating to the natural history of the syndrome. As the field of HCT evolves to allow for the incorporation of alternate graft sources, for expansion of donor options to include unrelated and mismatched donors, and for use of reduced-intensity conditioning or reduced toxicity myeloablative regimens, we have yet to determine if these advances modify the disease-specific course. While long-term outcomes of these patients are often included under one umbrella, this article seeks to address disease-specific post-HCT outcomes within IBMFS.
Topics: Humans; Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow; Congenital Bone Marrow Failure Syndromes; Hemoglobinuria, Paroxysmal; Hematopoietic Stem Cell Transplantation; Disease Progression
PubMed: 38066882
DOI: 10.1182/hematology.2023000471 -
Hematology/oncology Clinics of North... May 2024This article explores the multifaceted landscape of oral cancer precursor syndromes. Hereditary disorders like dyskeratosis congenita and Fanconi anemia increase the... (Review)
Review
This article explores the multifaceted landscape of oral cancer precursor syndromes. Hereditary disorders like dyskeratosis congenita and Fanconi anemia increase the risk of malignancy. Oral potentially malignant disorders, notably leukoplakia, are discussed as precursors influenced by genetic and immunologic facets. Molecular insights delve into genetic mutations, allelic imbalances, and immune modulation as key players in precancerous progression, suggesting potential therapeutic targets. The article navigates the controversial terrain of management strategies of leukoplakia, encompassing surgical resection, chemoprevention, and immune modulation, while emphasizing the ongoing challenges in developing effective, evidence-based preventive approaches.
PubMed: 38705773
DOI: 10.1016/j.hoc.2024.04.001 -
G3 (Bethesda, Md.) Nov 2023Aging is the consequence of intra- and extracellular events that promote cellular senescence. Dyskeratosis congenita (DC) is an example of a premature aging disorder...
Aging is the consequence of intra- and extracellular events that promote cellular senescence. Dyskeratosis congenita (DC) is an example of a premature aging disorder caused by underlying telomere/telomerase-related mutations. Cells from these patients offer an opportunity to study telomere-related aging and senescence. Our previous work has found that telomere shortening stimulates DNA damage responses (DDRs) and increases reactive oxygen species (ROS), thereby promoting entry into senescence. This work also found that telomere elongation via TERT expression, the catalytic component of the telomere-elongating enzyme telomerase, or p53 shRNA could decrease ROS by disrupting this telomere-DDR-ROS pathway. To further characterize this pathway, we performed a CRISPR/Cas9 knockout screen to identify genes that extend life span in DC cells. Of the cellular clones isolated due to increased life span, 34% had a guide RNA (gRNA) targeting CEBPB, while gRNAs targeting WSB1, MED28, and p73 were observed multiple times. CEBPB is a transcription factor associated with activation of proinflammatory response genes suggesting that inflammation may be present in DC cells. The inflammatory response was investigated using RNA sequencing to compare DC and control cells. Expression of inflammatory genes was found to be significantly elevated (P < 0.0001) in addition to a key subset of these inflammation-related genes [IL1B, IL6, IL8, IL12A, CXCL1 (GROa), CXCL2 (GROb), and CXCL5]. which are regulated by CEBPB. Exogenous TERT expression led to downregulation of RNA/protein CEBPB expression and the inflammatory response genes suggesting a telomere length-dependent mechanism to regulate CEBPB. Furthermore, unlike exogenous TERT and p53 shRNA, CEBPB shRNA did not significantly decrease ROS suggesting that CEBPB's contribution in DC cells' senescence is ROS independent. Our findings demonstrate a key role for CEBPB in engaging senescence by mobilizing an inflammatory response within DC cells.
Topics: Humans; Reactive Oxygen Species; Dyskeratosis Congenita; Telomerase; Tumor Suppressor Protein p53; Mutation; Telomere; RNA, Small Interfering; Fibroblasts; Inflammation; Mediator Complex; CCAAT-Enhancer-Binding Protein-beta
PubMed: 37717172
DOI: 10.1093/g3journal/jkad207