scholarly journals PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Olivia Cypris ◽  
Monika Eipel ◽  
Julia Franzen ◽  
Corinna Rösseler ◽  
Vithurithra Tharmapalan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Marrow ◽  
Neuronal Differentiation ◽  
Bone Marrow Failure ◽  
Premature Aging ◽  
Telomere Attrition ◽  
Bone Marrow Failure Syndromes ◽  
Epigenetic Age ◽  
Premature Aging Syndromes ◽  
Aberrant Dna Methylation

Abstract Background Dyskeratosis congenita (DKC) and idiopathic aplastic anemia (AA) are bone marrow failure syndromes that share characteristics of premature aging with severe telomere attrition. Aging is also reflected by DNA methylation changes, which can be utilized to predict donor age. There is evidence that such epigenetic age predictions are accelerated in premature aging syndromes, but it is yet unclear how this is related to telomere length. DNA methylation analysis may support diagnosis of DKC and AA, which still remains a challenge for these rare diseases. Results In this study, we analyzed blood samples of 70 AA and 18 DKC patients to demonstrate that their epigenetic age predictions are overall increased, albeit not directly correlated with telomere length. Aberrant DNA methylation was observed in the gene PRDM8 in DKC and AA as well as in other diseases with premature aging phenotype, such as Down syndrome and Hutchinson-Gilford-Progeria syndrome. Aberrant DNA methylation patterns were particularly found within subsets of cell populations in DKC and AA samples as measured with barcoded bisulfite amplicon sequencing (BBA-seq). To gain insight into the functional relevance of PRDM8, we used CRISPR/Cas9 technology to generate induced pluripotent stem cells (iPSCs) with heterozygous and homozygous knockout. Loss of PRDM8 impaired hematopoietic and neuronal differentiation of iPSCs, even in the heterozygous knockout clone, but it did not impact on epigenetic age. Conclusion Taken together, our results demonstrate that epigenetic aging is accelerated in DKC and AA, independent from telomere attrition. Furthermore, aberrant DNA methylation in PRDM8 provides another biomarker for bone marrow failure syndromes and modulation of this gene in cellular subsets may be related to the hematopoietic and neuronal phenotypes observed in premature aging syndromes. Graphical abstract

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.

Bone Marrow Failure Syndromes

2021 ◽  
pp. 43-61
Author(s):  
Amy E. Geddis ◽  
Meera Srikanthan ◽  
Katie Bergstrom
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Bone Marrow Failure Syndromes

scholarly journals Androgen therapy in inherited bone marrow failure syndromes: analysis from the Canadian Inherited Marrow Failure Registry

2020 ◽  
Vol 189 (5) ◽  
pp. 976-981 ◽  
Author(s):  
Albert Català ◽  
Salah S. Ali ◽  
Geoffrey D. E. Cuvelier ◽  
MacGregor Steele ◽  
Robert J. Klaassen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Androgen Therapy ◽  
Bone Marrow Failure Syndromes

scholarly journals Monitoring and treatment of MDS in genetically susceptible persons

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 105-109 ◽  
Author(s):  
Stella M. Davies
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Bone Marrow Failure ◽  
Treatment Strategies ◽  
Informed Choice ◽  
Dyskeratosis Congenita ◽  
Careful Consideration ◽  
Host Susceptibility ◽  
Bone Marrow Failure Syndromes ◽  
Severe Infections

Abstract Genetic susceptibility to myelodysplastic syndrome (MDS) occurs in children with inherited bone marrow failure syndromes, including Fanconi anemia, Shwachman Diamond syndrome, and dyskeratosis congenita. Available evidence (although not perfect) supports annual surveillance of the blood count and bone marrow in affected persons. Optimal treatment of MDS in these persons is most commonly transplantation. Careful consideration must be given to host susceptibility to DNA damage when selecting a transplant strategy, because significant dose reductions and avoidance of radiation are necessary. Transplantation before evolution to acute myeloid leukemia (AML) is optimal, because outcomes of AML are extremely poor. Children and adults can present with germline mutations in GATA2 and RUNX1, both of which are associated with a 30% to 40% chance of evolution to MDS. GATA2 deficiency may be associated with a clinically important degree of immune suppression, which can cause severe infections that can complicate transplant strategies. GATA2 and RUNX1 deficiency is not associated with host susceptibility to DNA damage, and therefore, conventional treatment strategies for MDS and AML can be used. RUNX1 deficiency has a highly variable phenotype, and MDS can occur in childhood and later in adulthood within the same families, making annual surveillance with marrow examination burdensome; however, such strategies should be discussed with affected persons, allowing an informed choice.

scholarly journals The clinical impact of copy number variants in inherited bone marrow failure syndromes

2017 ◽  
Vol 2 (1) ◽  
Author(s):  
Nicolas Waespe ◽  
Santhosh Dhanraj ◽  
Manju Wahala ◽  
Elena Tsangaris ◽  
Tom Enbar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Copy Number ◽  
Bone Marrow Failure ◽  
Copy Number Variants ◽  
Clinical Impact ◽  
Bone Marrow Failure Syndromes
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