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Westin, I. M., Landfors, M., Giannopoulos, A., Viberg, A., Osterman, P., Byström, B., . . . Golovleva, I. (2023). DNA methylation changes and increased mRNA expression of coagulation proteins, factor V and thrombomodulin in Fuchs endothelial corneal dystrophy. Cellular and Molecular Life Sciences (CMLS), 80(3), Article ID 62.
Open this publication in new window or tab >>DNA methylation changes and increased mRNA expression of coagulation proteins, factor V and thrombomodulin in Fuchs endothelial corneal dystrophy
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2023 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 80, no 3, article id 62Article in journal (Refereed) Published
Abstract [en]

Late-onset Fuchs endothelial corneal dystrophy (FECD) is a disease affecting the corneal endothelium (CE), associated with a cytosine-thymine-guanine repeat expansion at the CTG18.1 locus in the transcription factor 4 (TCF4) gene. It is unknown whether CTG18.1 expansions affect global methylation including TCF4 gene in CE or whether global CE methylation changes at advanced age. Using genome-wide DNA methylation array, we investigated methylation in CE from FECD patients with CTG18.1 expansions and studied the methylation in healthy CE at different ages. The most revealing DNA methylation findings were analyzed by gene expression and protein analysis. 3488 CpGs had significantly altered methylation pattern in FECD though no substantial changes were found in TCF4. The most hypermethylated site was in a predicted promoter of aquaporin 1 (AQP1) gene, and the most hypomethylated site was in a predicted promoter of coagulation factor V (F5 for gene, FV for protein). In FECD, AQP1 mRNA expression was variable, while F5 gene expression showed a ~ 23-fold increase. FV protein was present in both healthy and affected CE. Further gene expression analysis of coagulation factors interacting with FV revealed a ~ 34-fold increase of thrombomodulin (THBD). THBD protein was detected only in CE from FECD patients. Additionally, we observed an age-dependent hypomethylation in elderly healthy CE.Thus, tissue-specific genome-wide and gene-specific methylation changes associated with altered gene expression were discovered in FECD. TCF4 pathological methylation in FECD because of CTG18.1 expansion was ruled out.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
Coagulation factors; DNA methylation; Factor V; Fuchs dystrophy; Thrombomodulin; Transcription factor 4 (TCF4); Trinucleotide repeat disorder
National Category
Medical Genetics
Research subject
Medical Genetics; Medical Genetics
Identifiers
urn:nbn:se:umu:diva-200178 (URN)10.21203/rs.3.rs-1758860/v1 (DOI)000929515100001 ()36773096 (PubMedID)2-s2.0-85147894855 (Scopus ID)
Funder
Region VästerbottenUmeå UniversityStiftelsen Kronprinsessan Margaretas arbetsnämnd för synskadadeThe Kempe Foundations
Note

Originally included in thesis in manuscript form. 

Available from: 2022-10-12 Created: 2022-10-12 Last updated: 2023-09-05Bibliographically approved
Carlund, O., Norberg, A., Osterman, P., Landfors, M., Degerman, S. & Hultdin, M. (2023). DNA methylation variations and epigenetic aging in telomere biology disorders. Scientific Reports, 13(1), Article ID 7955.
Open this publication in new window or tab >>DNA methylation variations and epigenetic aging in telomere biology disorders
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2023 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, no 1, article id 7955Article in journal (Refereed) Published
Abstract [en]

Telomere Biology Disorders (TBDs) are characterized by mutations in telomere-related genes leading to short telomeres and premature aging but with no strict correlation between telomere length and disease severity. Epigenetic alterations are also markers of aging and we aimed to evaluate whether DNA methylation (DNAm) could be part of the pathogenesis of TBDs. In blood from 35 TBD cases, genome-wide DNAm were analyzed and the cases were grouped based on relative telomere length (RTL): short (S), with RTL close to normal controls, and extremely short (ES). TBD cases had increased epigenetic age and DNAm alterations were most prominent in the ES-RTL group. Thus, the differentially methylated (DM) CpG sites could be markers of short telomeres but could also be one of the mechanisms contributing to disease phenotype since DNAm alterations were observed in symptomatic, but not asymptomatic, cases with S-RTL. Furthermore, two or more DM-CpGs were identified in four genes previously linked to TBD or telomere length (PRDM8, SMC4, VARS, and WNT6) and in three genes that were novel in telomere biology (MAS1L, NAV2, and TM4FS1). The DM-CpGs in these genes could be markers of aging in hematological cells, but they could also be of relevance for the progression of TBD.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-209273 (URN)10.1038/s41598-023-34922-1 (DOI)000992335400030 ()37193737 (PubMedID)2-s2.0-85159474361 (Scopus ID)
Funder
The Kempe FoundationsCancerforskningsfonden i NorrlandUmeå UniversityRegion Västerbotten
Available from: 2023-06-08 Created: 2023-06-08 Last updated: 2023-09-05Bibliographically approved
Provez, L., Putteman, T., Landfors, M., Roels, J., Reunes, L., T’Sas, S., . . . Van Vlierberghe, P. (2023). Pre-clinical evaluation of the hypomethylating agent decitabine for the treatment of t-cell lymphoblastic lymphoma. Cancers, 15(3), Article ID 647.
Open this publication in new window or tab >>Pre-clinical evaluation of the hypomethylating agent decitabine for the treatment of t-cell lymphoblastic lymphoma
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2023 (English)In: Cancers, ISSN 2072-6694, Vol. 15, no 3, article id 647Article in journal (Refereed) Published
Abstract [en]

T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, often diagnosed at a young age. Patients are treated with intensive chemotherapy, potentially followed by a hematopoietic stem cell transplantation. Although prognosis of T-LBL has improved with intensified treatment protocols, they are associated with side effects and 10–20% of patients still die from relapsed or refractory disease. Given this, the search toward less toxic anti-lymphoma therapies is ongoing. Here, we targeted the recently described DNA hypermethylated profile in T-LBL with the DNA hypomethylating agent decitabine. We evaluated the anti-lymphoma properties and downstream effects of decitabine, using patient derived xenograft (PDX) models. Decitabine treatment resulted in prolonged lymphoma-free survival in all T-LBL PDX models, which was associated with downregulation of the oncogenic MYC pathway. However, some PDX models showed more benefit of decitabine treatment compared to others. In more sensitive models, differentially methylated CpG regions resulted in more differentially expressed genes in open chromatin regions. This resulted in stronger downregulation of cell cycle genes and upregulation of immune response activating transcripts. Finally, we suggest a gene signature for high decitabine sensitivity in T-LBL. Altogether, we here delivered pre-clinical proof of the potential use of decitabine as a new therapeutic agent in T-LBL.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
decitabine, DNA methylation, T-LBL
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-205009 (URN)10.3390/cancers15030647 (DOI)000933785600001 ()2-s2.0-85147801370 (Scopus ID)
Funder
EU, European Research Council, StG-639784Swedish Childhood Cancer Foundation, PR 2021-0049Swedish Cancer Society, 20-1053-PJThe Kempe Foundations, JCK-1833EU, Horizon 2020
Available from: 2023-02-22 Created: 2023-02-22 Last updated: 2024-03-26Bibliographically approved
Schäfer Hackenhaar, F., Josefsson, M., Nordin Adolfsson, A., Landfors, M., Kauppi, K., Porter, T., . . . the Australian Imaging Biomarkers and Lifestyle Study, . (2023). Sixteen-year longitudinal evaluation of blood-based DNA methylation biomarkers for early prediction of Alzheimer’s disease. Journal of Alzheimer's Disease, 94(4), 1443-1464
Open this publication in new window or tab >>Sixteen-year longitudinal evaluation of blood-based DNA methylation biomarkers for early prediction of Alzheimer’s disease
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2023 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 94, no 4, p. 1443-1464Article in journal (Refereed) Published
Abstract [en]

Background: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, hasshown promise for Alzheimer’s disease (AD) prediction.Objective: Testing long-term predictive ability (>15 years) of existing DNAm-based epigenetic age acceleration (EAA)measures and identifying novel early blood-based DNAm AD-prediction biomarkers.

Methods: EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models(LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16years before clinical onset, and post-onset follow-up. NovelDNAmbiomarkers were generated with epigenome-wide LMMs,and Sparse Partial Least Squares Discriminant Analysis applied at pre- (10–16 years), and post-AD-onset time-points.

Results: EAA did not differentiate cases from controls during the follow-up time (p > 0.05). Three new DNA biomarkersshowed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions(p-values: 0.022-<0.00001). Our longitudinally-derived panel replicated nominally (p = 0.012) in an external cohort (n = 146cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOE 4-carriership(OR = 1.38 per 1 SD DNAmscore increase versus OR= 13.58 for 4-allele carriage; AUCs = 77.2% versus 87.0%). Literaturereview showed low overlap (n = 4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with ouridentified CpGs.

Conclusion: The limited predictive value of EAA for AD extends prior findings by considering a longer follow-up time, andwith appropriate control for age, sex, APOE, and blood-cell proportions. Results also highlight challenges with replicatingdiscriminatory or predictive CpGs across studies.

Place, publisher, year, edition, pages
IOS Press, 2023
Keywords
Alzheimer’s disease, biomarkers, DNA methylation, epigenomics, longitudinal studies
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-214007 (URN)10.3233/jad-230039 (DOI)37393498 (PubMedID)2-s2.0-85168428453 (Scopus ID)
Funder
Swedish Research Council, 2018-01729The Kempe Foundations, JCK-1922.1
Available from: 2023-09-02 Created: 2023-09-02 Last updated: 2024-04-08Bibliographically approved
Framme, J. L., Lundqvist, C., Lundell, A.-C., van Schouwenburg, P. A., Lemarquis, A. L., Thörn, K., . . . Ekwall, O. (2022). Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs. Journal of Clinical Immunology, 42, 618-633
Open this publication in new window or tab >>Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs
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2022 (English)In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 42, p. 618-633Article in journal (Refereed) Published
Abstract [en]

Background: Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS).

Purpose: To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS.

Methods: Subjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed.

Results: At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells.

Conclusions: This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring.

Clinical Implications: This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices.

Place, publisher, year, edition, pages
Springer, 2022
Keywords
22q11.2 deletion syndrome, DiGeorge syndrome, long-term outcome, newborn screening, severe combined immunodeficiency, T lymphopenia, TREC
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-192261 (URN)10.1007/s10875-021-01201-5 (DOI)000749126700001 ()35080750 (PubMedID)2-s2.0-85123620385 (Scopus ID)
Funder
Swedish Research Council, 2018-02752Cancerforskningsfonden i Norrland, AMP 20-1000
Available from: 2022-03-11 Created: 2022-03-11 Last updated: 2022-07-12Bibliographically approved
Henckel, E., James, A., Konradsen, J. R., Nordlund, B., Kjellberg, M., Berggren-Broström, E., . . . Bohlin, K. (2021). A novel association between ykl-40, a marker of structural lung disease, and short telomere length in 10-year-old children with bronchopulmonary dysplasia. Children, 8(2), Article ID 80.
Open this publication in new window or tab >>A novel association between ykl-40, a marker of structural lung disease, and short telomere length in 10-year-old children with bronchopulmonary dysplasia
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2021 (English)In: Children, E-ISSN 2227-9067, Vol. 8, no 2, article id 80Article in journal (Refereed) Published
Abstract [en]

Extremely preterm infants are born with immature lungs and are exposed to an inflammatory environment as a result of oxidative stress. This may lead to airway remodeling, cellular aging and the development of bronchopulmonary dysplasia (BPD). Reliable markers that predict the long-term consequences of BPD in infancy are still lacking. We analyzed two biomarkers of cellular aging and lung function, telomere length and YKL-40, respectively, at 10 years of age in children born preterm with a history of BPD (n = 29). For comparison, these markers were also evaluated in sex-and-age-matched children born at term with childhood asthma (n = 28). Relative telomere length (RTL) was measured in whole blood with qPCR and serum YKL-40 with ELISA, and both were studied in relation to gas exchange and the regional ventilation/perfusion ratio using three-dimensional V/Q-scintigraphy (single photon emission computer tomography, SPECT) in children with BPD. Higher levels of YKL-40 were associated with shorter leukocyte RTL (Pearson’s correlation: −0.55, p = 0.002), but were not associated with a lower degree of matching between ventilation and perfusion within the lung. Serum YKL-40 levels were significantly higher in children with BPD compared to children with asthma (17.7 vs. 13.2 ng/mL, p < 0.01). High levels of YKL-40 and short RTLs were associated to the need for ventilatory support more than 1 month in the neonatal period (p < 0.01). The link between enhanced telomere shortening in childhood and structural remodeling of the lung, as observed in children with former BPD but not in children with asthma at the age of 10 years, suggests altered lung development related to prematurity and early life inflammatory exposure. In conclusion, relative telomere length and YKL-40 may serve as biomarkers of altered lung development as a result of early-life inflammation in children with a history of prematurity.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
Biomarker, Bronchopulmonary dysplasia, Inflammation-accelerated aging, Lung function, Oxidative stress, Preterm, SPECT, Telomere length, V/Q ratio, YKL-40
National Category
Respiratory Medicine and Allergy Pediatrics
Research subject
Pediatrics
Identifiers
urn:nbn:se:umu:diva-186912 (URN)10.3390/children8020080 (DOI)000622356100001 ()2-s2.0-85112470214 (Scopus ID)
Available from: 2021-08-26 Created: 2021-08-26 Last updated: 2023-10-05Bibliographically approved
Bovinder Ylitalo, E., Thysell, E., Landfors, M., Brattsand, M., Jernberg, E., Crnalic, S., . . . Wikström, P. (2021). A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer. Clinical Epigenetics, 13(1), Article ID 133.
Open this publication in new window or tab >>A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer
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2021 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 13, no 1, article id 133Article in journal (Refereed) Published
Abstract [en]

Background: Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity.

Materials and methods: Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity.

Results: Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT.

Conclusions: A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.

Place, publisher, year, edition, pages
BioMed Central, 2021
Keywords
Androgen receptor, DNA methylation, Gene expression, MetA, Metastasis, MetB, MetC, Prognosis, Prostate cancer, Subtypes
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-185893 (URN)10.1186/s13148-021-01119-0 (DOI)000670704300001 ()34193246 (PubMedID)2-s2.0-85109041809 (Scopus ID)
Available from: 2021-07-12 Created: 2021-07-12 Last updated: 2023-09-05Bibliographically approved
Pudas, S., Josefsson, M., Nordin Adolfsson, A., Landfors, M., Kauppi, K., Veng-Taasti, L. M., . . . Degerman, S. (2021). Short leukocyte telomeres, but not telomere attrition rates, predict memory decline in the 20-year longitudinal Betula study. The journals of gerontology. Series A, Biological sciences and medical sciences, 76(6), 955-963
Open this publication in new window or tab >>Short leukocyte telomeres, but not telomere attrition rates, predict memory decline in the 20-year longitudinal Betula study
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2021 (English)In: The journals of gerontology. Series A, Biological sciences and medical sciences, ISSN 1079-5006, E-ISSN 1758-535X, Vol. 76, no 6, p. 955-963Article in journal (Refereed) Published
Abstract [en]

Leukocyte telomere length (LTL) is a proposed biomarker for aging-related disorders, including cognitive decline and dementia. Long-term longitudinal studies measuring intra-individual changes in both LTL and cognitive outcomes are scarce, precluding strong conclusions about a potential aging-related relationship between LTL shortening and cognitive decline. This study investigated associations between baseline levels and longitudinal changes in LTL and memory performance across an up to 20-year follow-up in 880 dementia-free participants from a population-based study (mean baseline age: 56.8 years, range: 40–80; 52% female). Shorter baseline LTL significantly predicted subsequent memory decline (r = .34, 95% confidence interval: 0.06, 0.82), controlling for age, sex, and other relevant covariates. No significant associations were however observed between intra-individual changes in LTL and memory, neither concurrently nor with a 5-year time-lag between LTL shortening and memory decline. These results support the notion of short LTL as a predictive factor for aging-related memory decline, but suggest that LTL dynamics in adulthood and older age may be less informative of cognitive outcomes in aging. Furthermore, the results highlight the importance of long-term longitudinal evaluation of outcomes in biomarker research.

Place, publisher, year, edition, pages
Oxford University Press, 2021
Keywords
Cognitive aging, Leukocyte telomere length, Longitudinal, Memory, Population-based
National Category
Gerontology, specialising in Medical and Health Sciences Geriatrics Neurosciences
Research subject
medical behavioral science; Geriatrics; Psychology
Identifiers
urn:nbn:se:umu:diva-181484 (URN)10.1093/gerona/glaa322 (DOI)000659456700002 ()33367599 (PubMedID)2-s2.0-85107088699 (Scopus ID)
Funder
Swedish Research Council, 2018-01729Region Västerbotten, RV-735451, RV-453141, RV-225461
Available from: 2021-03-13 Created: 2021-03-13 Last updated: 2024-04-08Bibliographically approved
Schäfer Hackenhaar, F., Josefsson, M., Nordin Adolfsson, A., Landfors, M., Kauppi, K., Hultdin, M., . . . Pudas, S. (2021). Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers. Alzheimer's Research & Therapy, 13, Article ID 130.
Open this publication in new window or tab >>Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers
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2021 (English)In: Alzheimer's Research & Therapy, E-ISSN 1758-9193, Vol. 13, article id 130Article in journal (Refereed) Published
Abstract [en]

Background: Leukocyte telomere length (LTL) has been shown to predict Alzheimer’s disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor.

Methods: We analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards.

Results: After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1–24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404–7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947–2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD.

Conclusions: Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2021
Keywords
Leukocyte telomere length, Dementia, Risk factors, Time-to-event analysis, Competing risks, Vascular dementia, Death
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-186769 (URN)10.1186/s13195-021-00871-y (DOI)000673978800001 ()34266503 (PubMedID)2-s2.0-85110170246 (Scopus ID)
Note

Correction: Hackenhaar, F.S., Josefsson, M., Adolfsson, A.N. et al. Correction: Short leukocyte telomeres predict 25-year Alzheimer’s disease incidence in non-APOE ε4-carriers. Alz Res Therapy 16, 39 (2024). DOI: 10.1186/s13195-024-01388-w

Available from: 2021-08-20 Created: 2021-08-20 Last updated: 2024-04-08Bibliographically approved
Roels, J., Thénoz, M., Szarzyńska, B., Landfors, M., De Coninck, S., Demoen, L., . . . Van Vlierberghe, P. (2020). Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia. Blood cancer discovery, 1(3), 274-289
Open this publication in new window or tab >>Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia
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2020 (English)In: Blood cancer discovery, ISSN 2643-3249, Vol. 1, no 3, p. 274-289Article in journal (Refereed) Published
Abstract [en]

Cancer cells display DNA hypermethylation at specific CpG islands in comparison to their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T-cells and which display a reciprocal association with H3K27me3 binding. In addition, we revealed that this aberrant methylation profile reflects the epigenetic history of T-ALL and is established already in pre-leukemic, self-renewing thymocytes that precede T-ALL development. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature in T-ALL is completely resistant to the FDA-approved hypomethylating agent Decitabine. Altogether, we here provide conceptual evidence for the involvement of a pre-leukemic phase characterized by self-renewing thymocytes in the pathogenesis of human T-ALL.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2020
Keywords
DNA methylation, Decitabine, T-ALL, aging, self-renewing thymocytes
National Category
Cancer and Oncology Hematology
Identifiers
urn:nbn:se:umu:diva-176999 (URN)10.1158/2643-3230.BCD-20-0059 (DOI)000713094100007 ()33179015 (PubMedID)2-s2.0-85100020409 (Scopus ID)
Funder
The Kempe Foundations
Available from: 2020-11-24 Created: 2020-11-24 Last updated: 2023-09-19Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2783-0712

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