scholarly journals Nijmegen Breakage Syndrome (NBS) is a Telomeropathy: Analysis of Telomere Length in NBS Homo- and Heterozygotes and Humanized Nbs Mice

2019 ◽  
Author(s):  
Raneem Habib ◽  
Ryong Kim ◽  
Heidemarie Neitzel ◽  
Ilja Demuth ◽  
Krystyna Chrzanowska ◽  
...  
Keyword(s):  
Telomere Length ◽  
Cancer Incidence ◽  
Genetic Instability ◽  
Nijmegen Breakage Syndrome ◽  
Survival Times ◽  
Telomere Shortening ◽  
Cancer Rate ◽  
Telomere Attrition ◽  
After Cancer

AbstractThe autosomal recessive genetic disorder Nijmegen breakage syndrome (NBS) is characterized by a defect in DNA double-strand break repair protein nibrin and chromosome instability associated with a high predisposition to cancer. Here we hypothesized that impaired nibrin/MRE11/RAD50 telomere maintenance complex may also affect telomere length and modulate the cancer phenotype.Telomere length was studied in blood from 38 homozygous and 27 heterozygous individuals, in one homozygous fetus, and in sex NBS lymphoblastoid cell lines (all with the founder mutation c.657_661del5), and in three humanized Nbs mice, using qPCR, TRF and Q-FISH.Telomere lengths were markedly but uniformly reduced to 20-40% of healthy controls. There was no correlation between telomere length and severity of clinical phenotype or age of death. By contrast, individual patients with very short telomeres displayed long survival times after cancer manifestation. Mildly accelerated telomere attrition was found in older NBS heterozygotes. In the NBS-fetus, the spinal cord, brain and heart had the longest telomeres, skin the shortest. Humanized Nbs mice (with much longer telo-meres than those in human beings) did not show accelerated telomere attrition.Our data clearly show that NBS is a secondary telomeropathy with unique features. Te- lomere attrition in NBS may cause genetic instability and contribute to the high cancer incidence in NBS. On the other hand, short telomeres may prevent an even worse pheno-type when a tumor has developed. These data may help to understand the high cancer rate in NBS and also the bifunctional role of telomere shortening in cancerogenesis.Author SummaryDNA damage is harmful because it leads to mutations in genes that initiate or accelerate cancerogenesis. The devastating consequences of DNA damage are manifested in diseases with non-functional repair pathways such as Nijmegen breakage syndrome (NBS). A common feature of these diseases is a high tumor incidence. However, cancer incidence varies and is not clear why it is highest for NBS. In a previous study, we have shown that the underlying nebrin mutation not only leads to defective DNA repair but also to higher degree of oxidative stress that generates further DNA lesions. Nibrin may play also an important role in protecting chromosome ends, the telomeres, from inap-propriate DNA repair. Therefore we examined the telomere length in NBS and show markedly reduced values in affected patients but not in NBC mice (with much milder phenotype and longer telomeres). Telomere attrition contributes to genetic instability and may thus contribute to the high cancer incidence in NBS. Individual patients with very short telomeres, however, displayed long survival times after cancer manifestation. Thus, short telomeres may also prevent an even worse phenotype when a tumor has developed. These data are fundamental to understanding the high cancer rate in NBS and also the bifunctional role of telomere shortening in cancer.

Proaerolysin Multi Color Flow-Fish Reveals Shortened Telomere Length in GPI− as Compared to GPI+ Granulocytes from Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 171-171
Author(s):  
Fabian Beier ◽  
Stefan Balabanov ◽  
Tom Buckley ◽  
M. Rojewski ◽  
T. Becker ◽  
...  
Keyword(s):  
Telomere Length ◽  
Genetic Instability ◽  
Bone Marrow Failure ◽  
Response To Treatment ◽  
Disease Stage ◽  
Healthy Individuals ◽  
Color Flow ◽  
Telomere Shortening ◽  
Replicative Stress ◽  
Bone Marrow Failure Syndromes

Abstract Objective: Replication-dependent telomere shortening can result in cellular senescence or genetic instability. Telomere length both reflects and limits the replicative potential of normal somatic cells. Shortened telomeres have been linked to disease stage, degree of cytopenia as well as to response to treatment in patients with bone marrow failure syndromes. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by a somatic mutation in the X-linked PIG-A gene resulting in a deficiency of GPI-linked proteins on the cell surface. Pancytopenia in PNH is thought to result from an auto-immune mediated depletion of the GPI+ stem cell compartment. In the current study, we aimed to develop a methodology that allows the selective analysis of telomere length in granulocytes from patients with PNH dependent on GPI expression. The aim was to find out whether replicative stress posed on the residual GPI− HSC is reflected in shortened telomere length compared to their GPI+ counterparts. Methods: The telomere length of GPI+ and GPI− granulocytes of 12 patients with PNH and 22 healthy individuals was analysed. For this purpose, we developed Proearolysine Multi-color flow FISH which is based on the crosslinking of a fluorescence-labeled non-toxic derivative of the bacterial toxine Aerolysine (that selectively binds to the GPI anchor of cells) in combination with fluorescence in situ hybridization and flow cytometry. Results: We found significantly (p<0.05) shortened telomeres in GPI− granulocytes (6.68±0.3 telomere fluorescence unit (TFU), n=12) compared to age-matched healthy individuals (mean±S.E.: 7.73±0.8 TFU, n=22), but no significant shortening in GPI+ (7.06±0.3 TFU, n=12) granulocytes from PNH patients. Telomere length in GPI− granulocytes was found to be significantly shorter as compared to their GPI+ counterparts (deltaTEL: 0.38±0.1, p=0.002). These results were confirmed by Multi-color flow FISH using an anti-CD59 antibodies. Conclusion: Autoimmune-mediated damage to the GPI+ HSC compartment leads to compensatory hyperproliferation of predominantly residual GPI− HSC. In line with this hypothesis, coexisting GPI-negative HSC clones showed even more accelerated telomere shortening as compared to their GPI+ counterparts. Potentially, replicative exhaustion of individual HSC clones could contribute to disease progression in PNH. Whether acquired genetic instability due to progressive telomere shortening also accounts for an increased incidence of secondary clonal disorders will need to be evaluated in future prospective studies.

Extensive Chromosome Instability in Acute Myeloid Leukemia Is Associated with Critical Telomere Shortening.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3376-3376
Author(s):  
Susan J.J. Swiggers ◽  
Marianne A. Kuijpers ◽  
Maartje J. de Cort ◽  
Berna Beverloo ◽  
J. Mark J.M. Zijlmans
Keyword(s):  
Telomere Length ◽  
Reciprocal Translocation ◽  
Genetic Instability ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Chromosome Instability ◽  
Telomerase Activity ◽  
In Vitro Models ◽  
Telomere Shortening

Abstract Telomeres, the ends of linear chromosomes, have a critical role in protection against chromosome end-to-end fusion. Telomeres shorten in every cell division due to the end replication problem. Telomerase is a reverse transcriptase that adds telomeric DNA repeats to the ultimate chromosome end. In vitro models of long-term fibroblast cultures have identified two sequential mortality stages, senescence (M1) and crisis (M2). Senescence can be bypassed by loss of p53 or Rb function, whereas escape from crisis can only be achieved by activating a telomere maintenance mechanism, mostly telomerase reactivation. Cells that bypass senescence (M1) did not reactivate telomerase, resulting in further telomere shortening to a critical telomere length upon reaching crisis (M2). In these models, critical telomere shortening induces extensive chromosome instability, most likely via chromosome end-to-end fusions. Dicentric chromosomes lead to anaphase breakage-fusion-bridges resulting in multiple chromosomal aberrations. To investigate whether similar mechanisms may be involved in the development of genetic instability in human cancer, we studied telomere length and expression of critical telomeric proteins (TRF2 and POT1) in acute myeloid leukemia (AML) patients. AML is a good model for these studies since distinct subgroups of AML are characterized by either exchanges along chromosome arms (translocation or inversion), or by a complex karyotype with multiple chromosome aberrations. Groups were age-matched. Telomere length was studied in metaphase arrested leukemic cells using quantitative fluorescence in situ hybridization (Q-FISH) using a telomere-specific probe. Subsequently, metaphase spreads were hybridized with a leukemia-specific probe to confirm leukemic origin of each metaphase. Telomeres were significantly shorter in AML samples with multiple chromosomal abnormalities in comparison to AML samples with a reciprocal translocation/inversion or no abnormalities (mean±SEM=16±1.7 AFU, n=12 versus 29±4.3 AFU, n=18; p=0.015). Interestingly, telomerase activity level is significantly higher in AML samples with multiple chromosomal abnormalities, compared to AML samples with a reciprocal translocation or inversion (mean±SEM=330±95, n=11 versus 70±21, n=13; p=0.02). Expression levels of telomeric proteins TRF2 and POT1 were similar in these AML groups. Our observations suggest that, consistent with previous in vitro models in fibroblasts, critical telomere shortening may have a role in the development of genetic instability in human AML. Critically short telomeres in association with high levels of telomerase activity suggest that AML cells with multiple chromosomal abnormalities have bypassed crisis (M2). The longer telomeres and low levels of telomerase activity in AML cells with a reciprocal translocation or inversion suggest that they originate from an earlier stage, preceding crisis. Consequently, telomere length modulation may have a role in cancer prevention.

scholarly journals Telomeres, stem cells, and hematology

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 1759-1766 ◽  
Author(s):  
Peter M. Lansdorp
Keyword(s):  
Stem Cells ◽  
Telomere Length ◽  
Cellular Response ◽  
Germ Line ◽  
Critical Role ◽  
Somatic Cells ◽  
Growth Stimulation ◽  
Critical Function ◽  
Telomere Attrition

Telomeres are highly dynamic structures that adjust the cellular response to stress and growth stimulation based on previous cell divisions. This critical function is accomplished by progressive telomere shortening and DNA damage responses activated by chromosome ends without sufficient telomere repeats. Repair of critically short telomeres by telomerase or recombination is limited in most somatic cells, and apoptosis or cellular senescence is triggered when too many uncapped telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germ line that typically express high levels of telomerase. In somatic cells, the telomere length typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal cells in which malignant progression is facilitated by genome instability resulting from uncapped telomeres. The critical role of telomeres in cell proliferation and aging is illustrated in patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Here, the role of telomeres and telomerase in human biology is reviewed from a personal historical perspective.

scholarly journals Telomeres and Longevity: A Cause or an Effect?

2019 ◽  
Vol 20 (13) ◽  
pp. 3233 ◽  
Author(s):  
Huda Adwan Shekhidem ◽  
Lital Sharvit ◽  
Eva Leman ◽  
Irena Manov ◽  
Asael Roichman ◽  
...  
Keyword(s):  
Telomere Length ◽  
Ongoing Debate ◽  
Telomere Attrition ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Extreme Longevity ◽  
Linear Chromosomes ◽  
Biological State

Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a “biological thermometer” that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.

Longitudinal Changes In Telomere Length In Patients with Dyskeratosis Congenita

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2230-2230
Author(s):  
Blanche P Alter ◽  
Neelam Giri ◽  
Peter M. Lansdorp ◽  
Gabriela M. Baerlocher ◽  
Philip S Rosenberg ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Telomere Length ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Premature Aging ◽  
Bone Marrow Failure Syndrome ◽  
Cross Sectional ◽  
Telomere Shortening ◽  
Early Presentation ◽  
Telomere Attrition

Abstract Abstract 2230 Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome with a complex clinical phenotype, including dysplastic nails, lacy reticular pigmentation, and oral leukoplakia (the diagnostic triad). Numerous other physical abnormalities may be present, in addition to cytopenias due to bone marrow failure, and a high risk of leukemia or solid tumors. However, many patients have no physical findings at diagnosis. Patients with DC have very short telomeres, and approximately one-half have a mutation in one of six genes important in telomere biology. Telomere length in leukocyte subsets, measured by automated flow fluorescence in situ hybridization (flow-FISH), is both sensitive and specific for identifying individuals with DC. Telomeres consist of nucleotide repeats and a protein complex at chromosome ends that are critical in chromosomal stability which shorten during normal cell division. Cross-sectional studies of normal individuals suggest that telomere length decreases with age in a sigmoid pattern from birth to old age. In a cross-sectional analysis of 26 patients with DC, we previously observed that telomere length appeared to be stable or even to slightly increase with age (BP Alter et al, Blood 110:149, 2007). Similar results were shown in 23 different DC patients by others (M Bessler et al, FEBS Lett 2010 in press). We speculated that these data were influenced by early presentation (or recognition) of clinically more severe patients, while patients with similar telomere length who were clinically milder were identified at older ages. In this pilot study, we examined, for the first time, the longitudinal age-association of telomere attrition in nine patients with DC who were followed for five to seven years (currently 8 – 50 years of age). These include three patients with mutations in TERC, and two each with TINF2, TERT, and DKC1 mutations. When first studied, four had normal hematopoiesis, three moderate cytopenias, one was receiving androgens, and one was on transfusions. Subsequently, one with normal hematopoiesis developed mild thrombocytopenia, one who was on transfusions responded to androgens, and one with moderate aplastic anemia became severe. In all cases, telomere length decreased with age. In a linear regression model, the average annual decrease in telomere length in lymphocytes was 167 base pairs/year (bp/yr) + 104, similar to the rate in granulocytes, 159 + 92 bp/yr. According to the literature, the rate of telomere attrition in longitudinal studies in normal blood is ∼45-50 bp/yr, albeit by methods other than flow-FISH; the rate of telomere shortening appears to decrease with increasing age. The average patient Z-scores at the beginning of the study were -3.9 standard deviations below the median for age in healthy normal controls, and were -4.3 at the end, consistent with the impression that DC patient telomeres shorten somewhat more than expected from normal aging. These data support the hypothesis that the earlier cross-sectional results for patients with DC indeed were influenced by the cross-sectional rather than longitudinal nature of the data. The current longitudinal data suggest that telomere shortening could possibly be accelerated in patients with DC, but larger studies are required. Our results indicate that patients with DC have telomeres that are much shorter than normal for their age, and that over time they continue to shorten, consistent with DC being classified as a disorder of premature aging. Disclosures: Lansdorp: Repeat Diagnostics: Equity Ownership.

scholarly journals Nestling telomere length does not predict longevity, but covaries with adult body size in wild barn swallows

2013 ◽  
Vol 9 (5) ◽  
pp. 20130340 ◽  
Author(s):  
Manuela Caprioli ◽  
Maria Romano ◽  
Andrea Romano ◽  
Diego Rubolini ◽  
Rosita Motta ◽  
...  
Keyword(s):  
Body Size ◽  
Telomere Length ◽  
Large Body ◽  
Telomere Shortening ◽  
Rearing Conditions ◽  
Age Dependent ◽  
In The Wild ◽  
Barn Swallows ◽  
The Cost

Telomere length and dynamics are increasingly scrutinized as ultimate determinants of performance, including age-dependent mortality and fecundity. Few studies have investigated longevity in relation to telomere length (TL) in the wild and none has analysed longevity in relation to TL soon after hatching, despite the fact that telomere shortening may mostly occur early in life. We show that TL in nestling barn swallows ( Hirundo rustica ) in the wild does not predict longevity. However, TL positively covaries with body size, suggesting that individuals with large TL can afford to grow larger without paying the cost of reduced TL, and/or that benign rearing conditions ensure both large body size and low rates of telomere shortening. Overall, our study hints at a role of TL in developmental processes, but also indicates a need for further analyses to assess the expectation that TL in young individuals predicts longevity in the wild.

scholarly journals Parallel telomere shortening in multiple body tissues owing to malaria infection

2016 ◽  
Vol 283 (1836) ◽  
pp. 20161184 ◽  
Author(s):  
Muhammad Asghar ◽  
Vaidas Palinauskas ◽  
Nadège Zaghdoudi-Allan ◽  
Gediminas Valkiūnas ◽  
Andrey Mukhin ◽  
...  
Keyword(s):  
Telomere Length ◽  
Quantitative Polymerase Chain Reaction ◽  
Telomere Shortening ◽  
Tissue Samples ◽  
Telomere Attrition ◽  
Body Tissues ◽  
Increased Risk ◽  
Avian Malaria Parasite ◽  
Systemic Stress ◽  
The Impact

Several studies have shown associations between shorter telomere length in blood and weakened immune function, susceptibility to infections, and increased risk of morbidity and mortality. Recently, we have shown that malaria accelerates telomere attrition in blood cells and shortens lifespan in birds. However, the impact of infections on telomere attrition in different body tissues within an individual is unknown. Here, we tested whether malarial infection leads to parallel telomere shortening in blood and tissue samples from different organs. We experimentally infected siskins ( Spinus spinus ) with the avian malaria parasite Plasmodium ashfordi , and used real-time quantitative polymerase chain reaction (PCR) to measure telomere length in control and experimentally infected siskins. We found that experimentally infected birds showed faster telomere attrition in blood over the course of infection compared with control individuals (repeatedly measured over 105 days post-infection (DPI)). Shorter telomeres were also found in the tissue of all six major organs investigated (liver, lungs, spleen, heart, kidney, and brain) in infected birds compared with controls at 105 DPI. To the best of our knowledge, this is the first study showing that an infectious disease results in synchronous telomere shortening in the blood and tissue cells of internal organs within individuals, implying that the infection induces systemic stress. Our results have far-reaching implications for understanding how the short-term effects of an infection can translate into long-term costs, such as organ dysfunction, degenerative diseases, and ageing.

Telomere dynamics in Fancg-deficient mouse and human cells

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 3927-3935 ◽  
Author(s):  
Sonia Franco ◽  
Henri J. van de Vrugt ◽  
Piedad Fernández ◽  
Miguel Aracil ◽  
Fre Arwert ◽  
...  
Keyword(s):  
Telomere Length ◽  
Bone Marrow Cells ◽  
Human Cells ◽  
Telomere Maintenance ◽  
Deficient Mouse ◽  
Early Passage ◽  
Telomere Shortening ◽  
Hematopoietic Stem ◽  
Telomere Dynamics

Abstract A number of DNA repair proteins also play roles in telomere metabolism. To investigate whether the accelerated telomere shortening reported in Fanconi anemia (FA) hematopoietic cells relates to a direct role of the FA pathway in telomere maintenance, we have analyzed telomere dynamics in Fancg-deficient mouse and human cells. We show here that both hematopoietic (stem and differentiated bone marrow cells, B and T lymphocytes) and nonhematopoietic (germ cells, mouse embryonic fibroblasts [MEFs]) Fancg-/- mouse cells display normal telomere length, normal telomerase activity, and normal chromosome end-capping, even in the presence of extensive clastogen-induced cytogenetic instability (mitomycin C [MMC], gamma-radiation). In addition, telomerase-deficient MEFs with humanlike telomere length and decreased Fancg expression (G5 Terc-/-/Fancg shRNA3 MEFs) display normal telomere maintenance. Finally, early-passage primary fibroblasts from patients with FA of complementation group G as well as primary human cells with reduced FANCG expression (FANCG shRNA IMR90 cells) show no signs of telomere dysfunction. Our observations indicate that accelerated telomere shortening in patients with FA is not due to a role of FANCG at telomeres but instead may be secondary to the disease. These findings suggest that telomerase-based therapies could be useful prophylactic agents in FA aplastic anemia by preserving their telomere reserve in the context of the disease. (Blood. 2004;104:3927-3935)

scholarly journals Chromosome specific telomere lengths and the minimal functional telomere revealed by nanopore sequencing

2021 ◽  
Author(s):  
Samantha L. Sholes ◽  
Kayarash Karimian ◽  
Ariel Gershman ◽  
Thomas J. Kelly ◽  
Winston Timp ◽  
...  
Keyword(s):  
Telomere Length ◽  
Clonal Variation ◽  
Nanopore Sequencing ◽  
Biological Mechanisms ◽  
Specific Chromosome ◽  
Telomere Shortening ◽  
Long Read ◽  
Length Regulation ◽  
Telomere Length Regulation

We developed a method to tag telomeres and measure telomere length by nanopore sequencing in the yeast S. cerevisiae. Nanopore allows long read sequencing through the telomere, subtelomere and into unique chromosomal sequence, enabling assignment of telomere length to a specific chromosome end. We observed chromosome end specific telomere lengths that were stable over 120 cell divisions. These stable chromosome specific telomere lengths may be explained by stochastic clonal variation or may represent a new biological mechanism that maintains equilibrium unique to each chromosomes end. We examined the role of RIF1 and TEL1 in telomere length regulation and found that TEL1 is epistatic to RIF1 at most telomeres, consistent with the literature. However, at telomeres that lack subtelomeric Y' sequences, tel1Δ rif1Δ double mutants had a very small, but significant, increase in telomere length compared to the tel1Δ single mutant, suggesting an influence of Y' elements on telomere length regulation. We sequenced telomeres in a telomerase-null mutant (est2Δ) and found the minimal telomere length to be around 75bp. In these est2Δ mutants there were many apparent telomere recombination events at individual telomeres before the generation of survivors, and these events were significantly reduced in est2Δ rad52Δ double mutants. The rate of telomere shortening in the absence of telomerase was similar across all chromosome ends at about 5 bp per generation. This new method gives quantitative, high resolution telomere length measurement at each individual chromosome end, suggests possible new biological mechanisms regulating telomere length, and provides capability to test new hypotheses.

Premature Aging of Hematopoietic Cells in Long Term Survivors after HSCT with Chronic GVHD and a Female Donor.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 829-829 ◽  
Author(s):  
Gabriela M. Baerlocher ◽  
Alicia Rovo ◽  
Astrid Mueller ◽  
Sybille Matthey ◽  
Martin Stern ◽  
...  
Keyword(s):  
Telomere Length ◽  
Chronic Gvhd ◽  
Nkt Cells ◽  
Premature Aging ◽  
Telomere Shortening ◽  
Telomere Attrition ◽  
Female Donor ◽  
The Mean ◽  
Long Term Survivors

Abstract The establishment of donor-derived hematopoiesis in recipients of hematopoietic stem cell (HSC) transplantation (HSCT) involves extensive proliferation of HSCs and might lead to “premature aging” of hematopoietic cells. Telomere shortening as indicator of cell proliferation has been described after HSCT. The telomere attrition has mainly been observed during the first year after allogeneic HSCT. Thereafter, telomere length dynamics of recipients appeared not to differ from their donors. The aim of our cross-sectional study was to evaluate the telomere attrition in leukocyte subsets of very long term survivors (LTS) after HSCT in relation to donor/recipient age, sex, cell counts in peripheral blood, number of transplanted nucleated cells (NTNC), and occurrence of acute and chronic graft versus host disease (GVHD). Automated multicolour flow-FISH was used to measure the telomere length in granulocytes, naive T-cells, B-cells and NK/NKT-cells of 44 LTS and their HLA-identical sibling donors. At HSCT the median age of donors and recipients was 25.8 (2–46) and 26.8 years (5–50). The median follow-up after HSCT was 17.5 years (11–26). Four patients received HSCT for aplastic anemia, 40 for hematological malignancies. All patients received bone marrow as source of HSC and TBI was part of the conditioning in 39 (89%). Acute GVHD was observed in 31 (70%), and chronic GVHD in 22 (50%) patients. The age-matched and cell-type specific absolute telomere length values for recipients and donors fell between the 1st-99th percentile of the normal distribution. The telomere length (mean ± std) was significantly shorter in recipients as compared to their donors (p<0.01) for granulocytes (6.5±0.9 vs 7.1±0.9), T-cells (5.7±1.2 vs 6.6±1.2), B-cells (7.1±1.1 vs 7.8±1.1) and NK/NKT-cells (4.8±1.0 vs 5.6±1.3). The mean difference between recipients and donors for each subset of cells was between 0.6–0.9 kb. The mean telomere length of all subsets of cells was significantly shorter for males compared to females even though this difference was small. Age, sex of recipient, NTNC, and acute GVHD had no impact on telomere attrition. In all cell types except NK/NKT-cells we found a significant telomere shortening in recipients transplanted with a female donor (p<0.04) and in those with chronic GVHD (p<0.04). The telomere length difference between donor/recipient was most pronounced for recipients with the combination of a female donor and chronic GVHD (Figure 1). The loss in telomere length is more than twice for patients with a female donor and chronic GVHD compared to those with a male donor without chronic GVHD. In summary, our data reveal chronic GVHD and a female donor to be predictors for higher telomere attrition in LTS after HSCT. The more pronounced telomere attrition with a female donor and chronic GVHD corresponds to approximately 30–60 years of cell aging and raises once more the question of cellular immuno-senescence and its consequences in LTS of HSCT. Figure Figure

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