scholarly journals Moderate stem-cell telomere shortening rate postpones cancer onset in a stochastic model

2013 ◽  
Vol 88 (4) ◽  
Author(s):  
Simon Holbek ◽  
Kristian Moss Bendtsen ◽  
Jeppe Juul
2017 ◽  
Vol 9 (3) ◽  
pp. 129
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya

BACKGROUND: Aging per se is a risk factor for reduced cardiac function and heart diseases, even when adjusted for aging-associated cardiovascular risk factors. Accordingly, aging-related biochemical and cell-biological changes lead to pathophysiological conditions, especially reduced heart function and heart disease.CONTENT: Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1a and PGC-1b in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging.SUMMARY: The aging myocardium with telomere shortening and accumulation of senescent cells restricts the tissue regenerative ability, which contributes to systolic or diastolic heart failure. Moreover, patients with ion-channel defects might have genetic imbalance caused by oxidative stress-related accelerated telomere shortening, which may subsequently cause sudden cardiac death. Telomere length can serve as a marker for the biological status of previous cell divisions and DNA damage with inflammation and oxidative stress. It can be integrated into current risk prediction and stratification models for cardiovascular diseases and can be used in precise personalized treatments.KEYWORDS: aging, telomere, telomerase, aging heart, mitochondria, cardiac stem cell


2019 ◽  
Vol 6 ◽  
pp. 7-7 ◽  
Author(s):  
Ezzatollah Fathi ◽  
Hojjatollah Nozad Charoudeh ◽  
Zohreh Sanaat ◽  
Raheleh Farahzadi

2004 ◽  
Vol 279 (17) ◽  
pp. 17826-17833 ◽  
Author(s):  
Carmen Martin-Ruiz ◽  
Gabriele Saretzki ◽  
Joanne Petrie ◽  
Juliane Ladhoff ◽  
Jessie Jeyapalan ◽  
...  

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3809-3809
Author(s):  
Fabian Beier ◽  
Ralph P Schneider ◽  
Guntram Buesche ◽  
Jens Panse ◽  
Ulrich Germing ◽  
...  

Abstract Abstract 3809 Introduction: Myelodysplastic syndromes (MDS) are heterogeneous clonal stem cell disorders characterized by ineffective hematopoiesis and an increased risk for leukemic transformation. Lenalidomide (LEN) was found to be an effective treatment particularly in a subset of MDS patients with isolated 5q minus deletion (del5q). A high proportion of these patients show erythroid response with transfusion independence and even complete cytogenetic response (CCR). However, particularly in patients not responding to LEN, disease progression to acute leukemia is observed. Accelerated telomere length shortening is regularly observed in hematopoietic stem cell disorders with increased stem cell turnover and/or altered telomere maintenance. Dysfunctional telomeres have been found to play an important role in the development of chromosomal instability and malignant transformation. The aim of this study was to investigate telomere length as a potential predictive biomarker in MDS del5q patients treated with LEN with regard to disease progression and treatment response. Methods and Patients: Telomere length (TL) was determined using confocal Q-FISH on paraffin-embedded BM biopsies of 54 MDS patients enrolled in the LEMON5 study (NCT01081431). Criteria for study inclusion were isolated del5q, transfusion dependence of at least one unit per 8 weeks and IPSS low risk and intermediate-1. TL was analyzed in a blinded fashion on specimen obtained before treatment initiation with LEN, control biopsies of 11 patients with newly diagnosed Morbus Hodgkin without BM affection were used for age-adaption of TL. At the time of this preliminary analysis, the study is ongoing, initial clinical data were available for 94% (51/54) and detailed follow up data for 63% (34/54) of the patients with a median follow up of 22 months. Mean age of the MDS patients was 68.6 years (range 40–87) and average disease duration before enrolment was 2.9 years. Results: We found that TL of the 54 MDS patients was significantly shorter compared to the age-adjusted TL (−0.57 kb, p=0.02, n=54). Interestingly, analysis according to the respective IPSS showed significant shorter telomeres in the low risk group (−0.91 kb, p=0.04, n=27) than in the intermediate-1 group (−0.55 kb, p=0.24, n=19). Focusing on the peripheral blood counts, cut-off values were set according to the distribution pattern representing the approximate median value. Patients with ANC counts <2000/μl (−0.98 kb, p=0.03, n=27), haemoglobin values <9g/dl (−0.89 kb, p=0.02, n=26) and platelets counts <300/nl (−0.87 kb, p=0.01, n=27) had significantly shortened telomeres compared to the age-adjusted controls. In contrast, patients with ANC counts >2000/μl (0.06 kb, p=0.9, n=20), haemoglobin >9g/dl (−0.23 kb, p=0.23, n=25) and platelet counts >300/nl (−0.07 kb, p=0.58, n=24) did not differ from the age-adjusted TL. Furthermore, patients with a history of more than 2 years of MDS had significantly shortened age-adjusted telomere length (−0.94 kb, p=0.02, n=26), but that was not the case in patients with a short disease duration (<2 years; −0.32 kb, p=0.36, n=28). Interestingly, with regards to response to LEN, patients later achieving a CCR under LEN had significantly shortened TL at treatment initiation (−1.47 kb, n=14, p=0.005) whereas this was not the case in patients with no response, relapse or progressive disease during follow-up (−0.23 kb, n=20, p=0.62). Furthermore, correlation with treatment duration showed that patients receiving more than 12 cycles of LEN (in which 93%, i.e. 13/14 patients were responding) had significantly shorter telomeres before start of LEN (−1.41 kb, n=17, p=0.02) compared to the group of patients with less than 12 cycles (0.22 kb, n=14) in which 41%, i.e. 7/17 patients were responding. Conclusions: Patients with MDS and isolated del5q undergo significant telomere shortening. Using telomere length analysis on paraffin-embedded BM biopsies using confocal Q-FISH, we were able to identify a subgroup of patients with lower peripheral blood counts and accelerated TL shortening that seemed to preferentially profit from LEN treatment. In summary and pending further confirmation with longer follow up of this preliminary analysis within the ongoing LeMon5 study, we conclude that telomere length analysis may identify a distinct biological subentity of MDS del5q patients more likely to benefit from treatment with LEN. Disclosures: Germing: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Brümmendorf:Celgene: Research Funding.


Sign in / Sign up

Export Citation Format

Share Document